Synthesis, spectroscopic characterization and biological activity of cis-[Ru(hesperidin)(1,10‧-phenanthroline)2](PF6) complex

NASA Astrophysics Data System (ADS)

Oliveira, Regina M. M.; de Souza Daniel, Juliana F.; Carlos, Rose M.

2013-01-01

The new complex cis-[Ru(phen)2(hesperidin)](PF6), complex 1, was synthesized and characterized by analytical (ESI-MS+, EA (C, H, N)) and spectroscopic (FTIR, UV-vis, 1H and 13C NMR) techniques and cyclic voltammetry. Complex 1 is chemically stable in the solid state and in organic solvents such as ethanol, methanol, acetone, and acetonitrile, as shown by spectrophotometric analysis. 1 is also photochemically and chemically stable (pH effects) and more hydrosoluble (518.83 ± 0.91 g mL-1) than free hesperidin (5.92 g mL-1). In accordance with this, the lipophilicity value in aqueous-octanol solution for 1 was -1.28, indicating its high hydrophilic characteristic. Although complex 1 showed to be essentially noncytotoxic, IC50 > 1.0 mmol L-1 as evaluated in the human cervical cancer cells line HeLa, it exhibited a moderate capacity of inhibiting the catalytic activity of the acetylcholinaesterase enzyme, IC50 = 63.6 mol L-1. The Lineweaver-Burk plot and the respective secondary replot indicated that the AChE inhibition was noncompetitive and reversible. These findings shows that complexation of the hesperidin improves physicochemical characteristics and increases the perspectives for development and medical applications of new bioactive-metal complexes.

Intraocular distribution of topically applied hydrophilic and lipophilic substances in rat eyes.

PubMed

Abdul Nasir, Nurul Alimah; Agarwal, Puneet; Agarwal, Renu; Iezhitsa, Igor; Alyautdin, Renad; Nukolova, Natalia N; Chekhonin, Vladimir P; Mohd Ismail, Nafeeza

2016-10-01

Topical administration is the preferred route of drug delivery for ophthalmic ailments. However, poor permeation through ocular surface and significant systemic absorption, makes the topical drug delivery challenging. Furthermore, distribution of topically delivered drugs varies with their physicochemical properties and the type of formulation used. Hence, this study was done to understand the pattern of ocular drug distribution of topically applied hydrophilic and lipophilic substances in two different formulations. 5-Carboxyfluorescein and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate were used as representative candidates for hydrophilic and lipophilic substances, respectively. They were formulated in solution and liposomes. Single drop of either formulation containing hydrophilic or lipophilic substance was instilled topically, unilaterally to rat eyes. Subsequently, rats were sacrificed at 10, 30 and 120 min post-instillation. Eyes were cryosectioned and examined under confocal microscope to determine the fluorescence intensity in ocular tissues. Corneal permeation of hydrophilic and lipophilic substances in both formulations peaked at 30 min post-instillation. Liposomal-lipophilic dye and non-liposomal-hydrophilic dye showed better corneal distribution. Fluorescence was absent in contralateral eyes of non-liposomal-hydrophilic dye-treated animals but was present in contralateral eyes of liposomal-hydrophilic dye-treated animals. Fluorescence in contralateral eyes of liposomal-lipophilic dye-treated animals was significantly higher compared to non-liposomal-lipophilic dye-treated animals. Topically applied liposomal formulation of lipophilic substance provides higher corneal concentration of drug with lesser systemic absorption compared to its solution. For hydrophilic substance, topical use of solution provides greater corneal concentration compared to liposomes which is more likely to be absorbed systemically.

Differences in lung local dosimetry of the carcinogens benzo(a)pyrene and NNK

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dahl, A.R.; Muggenburg, B.A.; Thornton-Manning, J.R.

1996-12-31

A diffusion model predicts that highly lipophilic toxicants penetrate the comparatively thick epithelium of the conducting airways much more slowly than less lipophilic toxicants. To validate this model, the tracheal walls of a Beagle dog were sprayed with very small quantities of tritiated, highly lipophilic benzo(a)pyrene (BaP), moderately lipophilic pyrene, or slightly lipophilic 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone-(NNK). The concentration of the hydrocarbons and their metabolites were measured in the circulating blood for up to 6 hr, and tissue retention was determined at the end of the experiment. Differences in absorption of these compounds into blood were manifested in several independent measurements. Themore » highly lipophilic toxicant manifested: (1) a much slower penetration into azygous vein blood, the principal drainage system from the exposed area of the trachea; (2) a much slower appearance in the systemic circulation and (3) a much greater retention in the tracheal tissues at the end of the exposure. Increased retention mm in the airway mucosa allowed a grew fraction of lipophilic toxicants to be metabolized locally in the airway walls. This finding led us to conclude that, for example, if the carcinogens BaP and NNK are deposited at the same surface density on the airway mucosa, the highly lipophilic BaP will reach a far higher concentration in the airway epithelium than will the less lipophilic NNK. Such sharp differences in local dosimetry should be considered in order to improve the accuracy of risk assessment models for inhalants.« less

Effect of drying methods on total antioxidant capacity of bitter gourd (momordica charantia) fruit

NASA Astrophysics Data System (ADS)

Tan, Ee Shian; Abdullah, Aminah; Maskat, Mohammad Yusof

2013-11-01

The effect of thermal and non-thermal drying methods on hydrophilic and lipophilic antioxidant capacities of bitter gourd fruit was investigated in this study. The bitter gourd fruits were dried by following methods: (i) oven drying 40°C, (ii) oven drying 50°C, (iii) oven drying 60°C, (iv) microwave drying (medium low power), (v) microwave drying (medium power) and (vi) freeze drying. Pure acetone and hexane were used to extract the hydrophilic and lipophilic antioxidant compounds from dried bitter gourd fruits. Freeze dried extracts reported to have highest values in DPPH scavenging activity (hydrophilic and lipophilic fractions), FRAP (lipophilic fraction) and TPC (hydrophilic and lipophilic fraction). Thermal drying slightly increased the values of DPPH scavenging activity, FRAP and TPC assays for hydrophilic extracts. Results concluded bitter gourd fruit is a good source of natural antioxidants and its total antioxidant quality was most preserved by freeze drying. Additionally, the higher value reported in DPPH scavenging activity, FRAP and TPC assays for lipophilic extracts than the hydrophilic extracts suggested that the lipophilic antioxidant compounds of bitter gourd fruit might possess stronger antioxidant power than its counterpart.

A comprehensive overview on the micro- and nano-technological encapsulation advances for enhancing the chemical stability and bioavailability of carotenoids.

PubMed

Soukoulis, Christos; Bohn, Torsten

2018-01-02

Carotenoids are lipophilic secondary plant compounds, and their consumption within fruits and vegetables has been positively correlated with a decreased risk of developing several chronic diseases. However, their bioavailability is often compromised due to incomplete release from the food matrix, poor solubility and potential degradation during digestion. In addition, carotenoids in food products are prone to oxidative degradation, not only lowering the nutritional value of the product but also triggering other quality deteriorative changes, such as formation of lipid pro-oxidants (free radicals), development of discolorations or off-flavor defects. Encapsulation refers to a physicochemical process, aiming to entrap an active substance in structurally engineered micro- or nano-systems, in order to develop an effective thermodynamical and physical barrier against deteriorative environmental conditions, such as water vapor, oxygen, light, enzymes or pH. In this context, encapsulation of carotenoids has shown to be a very effective strategy to improve their chemical stability under common processing conditions including storage. In addition, encapsulation may also enhance bioavailability (via influencing bioaccessibility and absorption) of lipophilic bioactives, via modulating their release kinetics from the carrier system, solubility and interfacial properties. In the present paper, it is aimed to present the state of the art of carotenoid microencapsulation in order to enhance storability and bioavailability alike.

QSAR, QSPR and QSRR in Terms of 3-D-MoRSE Descriptors for In Silico Screening of Clofibric Acid Analogues.

PubMed

Di Tullio, Maurizio; Maccallini, Cristina; Ammazzalorso, Alessandra; Giampietro, Letizia; Amoroso, Rosa; De Filippis, Barbara; Fantacuzzi, Marialuigia; Wiczling, Paweł; Kaliszan, Roman

2012-07-01

A series of 27 analogues of clofibric acid, mostly heteroarylalkanoic derivatives, have been analyzed by a novel high-throughput reversed-phase HPLC method employing combined gradient of eluent's pH and organic modifier content. The such determined hydrophobicity (lipophilicity) parameters, log kw , and acidity constants, pKa , were subjected to multiple regression analysis to get a QSRR (Quantitative StructureRetention Relationships) and a QSPR (Quantitative Structure-Property Relationships) equation, respectively, describing these pharmacokinetics-determining physicochemical parameters in terms of the calculation chemistry derived structural descriptors. The previously determined in vitro log EC50 values - transactivation activity towards PPARα (human Peroxisome Proliferator-Activated Receptor α) - have also been described in a QSAR (Quantitative StructureActivity Relationships) equation in terms of the 3-D-MoRSE descriptors (3D-Molecule Representation of Structures based on Electron diffraction descriptors). The QSAR model derived can serve for an a priori prediction of bioactivity in vitro of any designed analogue, whereas the QSRR and the QSPR models can be used to evaluate lipophilicity and acidity, respectively, of the compounds, and hence to rational guide selection of structures of proper pharmacokinetics. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of Statin Treatment on Inflammation and Cardiac Function in Heart Failure: An Adjusted Indirect Comparison Meta-Analysis of Randomized Trials.

PubMed

Bonsu, Kwadwo Osei; Reidpath, Daniel Diamond; Kadirvelu, Amudha

2015-12-01

Statins are known to prevent heart failure (HF). However, it is unclear whether statins as class or type (lipophilic or hydrophilic) improve outcomes of established HF. The current meta-analysis was performed to compare the treatment effects of lipophilic and hydrophilic statins on inflammation and cardiac function in HF. Outcomes were indicators of cardiac function [changes in left ventricular ejection fraction (LVEF) and B-type natriuretic peptide (BNP)] and inflammation [changes in highly sensitive C-reactive protein (hsCRP) and interluekin-6 (IL-6)]. We conducted a search of PubMed, EMBASE, and the Cochrane databases until December 31, 2014 for randomized control trials (RCTs) of statin versus placebo in patients with HF. RCTs with their respective extracted information were dichotomized into statin type evaluated and analyzed separately. Outcomes were pooled with random effect approach, producing standardized mean differences (SMD) for each statin type. Using these pooled estimates, we performed adjusted indirect comparisons for each outcome. Data from 6214 patients from 19 trials were analyzed. Lipophilic statin was superior to hydrophilic statin treatment regarding follow-up LVEF (SMD, 4.54; 95% CI, 4.16-4.91; P < 0.001), BNP (SMD, -1.60; 95% CI, -2.56 to -0.65; P < 0.001), hsCRP (SMD, -1.13; 95% CI, -1.54 to -0.72; P < 0.001), and IL-6 (SMD, -3.75; 95% CI, -4.77 to -0.72; P < 0.001) in HF. Lipophilic statin produces greater treatment effects on cardiac function and inflammation compared with hydrophilic statin in patients with HF. Until data from adequately powered head-to-head trial of the statin types are available, our meta-analysis brings clinicians and researchers a step closer to the quest on which statin--lipophilic or hydrophilic--is associated with better outcomes in HF. © 2015 John Wiley & Sons Ltd.

Bovine and Porcine Transscleral Solute Transport: Influence of Lipophilicity and the Choroid–Bruch’s Layer

PubMed Central

Cheruvu, Narayan P. S.; Kompella, Uday B.

2012-01-01

Purpose To determine the influence of the choroid–Bruch’s layer and solute lipophilicity on in vitro transscleral drug permeability in bovine and porcine eyes. Methods The in vitro permeability of two VEGF inhibitory drugs, budesonide and celecoxib, which are lipophilic and neutral at physiologic pH, and of three marker solutes, 3H-mannitol (hydrophilic, neutral), sodium fluorescein (hydrophilic, anionic), and rhodamine 6G (lipophilic, cationic), were determined across freshly excised scleras, with or without the underlying choroid–Bruch’s layer. Select studies were performed using porcine sclera with and without choroid–Bruch’s layer. Neural retina was removed by exposure of the eyecup to isotonic buffer and wherever required, the retinal pigment epithelial (RPE) layer of the preparation was disrupted and removed by exposure to hypertonic buffer. Because of the poor solubility of celecoxib and budesonide, permeability studies were conducted with 5% wt/vol of hydroxypropyl-β-cyclodextrin (HPβCD). For other solutes, permeability studies were conducted, with and without HPβCD. Partitioning of the solutes into bovine sclera and choroid–Bruch’s layer was also determined. Results The calculated log (distribution coefficient) values were −2.89, −0.68, 2.18, 3.12, and 4.02 for mannitol, sodium fluorescein, budesonide, celecoxib, and rhodamine 6G, respectively. Removal of RPE was confirmed by transmission electron microscopy and differences in the transport of mannitol. The order of the permeability coefficients (Papp) across sclera and sclera–choroid–Bruch’s layers in bovine and porcine models was 3H-mannitol > fluorescein > budesonide > celecoxib > rhodamine 6G, with HPβCD, and 3H-mannitol > fluorescein > rhodamine 6G, without HPβCD. The presence of choroid–Bruch’s layer reduced the bovine scleral permeability by 2-, 8-, 16-, 36-, and 50-fold and porcine tissue permeability by 2-, 7-, 15-, 33-, and 40-fold, respectively, for mannitol, sodium fluorescein, budesonide, celecoxib, and rhodamine 6G. The partition coefficients measured in bovine tissues correlated positively with the log (distribution coefficient) and exhibited a trend opposite that of transport. The partition coefficient ratio of bovine choroid–Bruch’s layer to sclera was ~1, 1.5, 1.7, 2, and 3.5, respectively, for the solutes, as listed earlier. Conclusions The choroid–Bruch’s layer is a more significant barrier to drug transport than is sclera. It hinders the transport of lipophilic solutes, especially a cationic solute, more than hydrophilic solutes and in a more dramatic way than does sclera. The reduction in transport across this layer directly correlates with solute binding to the tissue. Understanding the permeability properties of sclera and underlying layers would be beneficial in designing better drugs for transscleral delivery. PMID:17003447

Disassembly Control of Saccharide-Based Amphiphiles Driven by Electrostatic Repulsion.

PubMed

Yamada, Taihei; Kokado, Kenta; Sada, Kazuki

2017-03-14

According to the design of disassembly using electrostatic repulsion, novel amphiphiles consisting of a lipophilic ion part and a hydrophilic saccharide part were synthesized via the facile copper-catalyzed click reaction, and their molecular assemblies in water and chloroform were studied. The amphiphiles exhibited a molecular orientation opposite to that of the conventional amphiphiles in each case. ζ Potential measurements indicated that the lipophilic ion part is exposed outside in chloroform. The size of a solvophobic part in the amphiphiles dominates the size of an assembling structure; that is, in water, these amphiphiles tethering different lengths of the saccharide part exhibited almost identical assembling size, whereas in chloroform, the size depends on the length of the saccharide part in the amphiphiles.

Quantitative structure toxicity relationships for phenols in isolated rat hepatocytes.

PubMed

Moridani, Majid Y; Siraki, Arno; O'Brien, Peter J

2003-05-06

Quantitative structure toxicity relationship (QSTR) equations were obtained to predict and describe the cytotoxicity of 31 phenols using logLD(50) as a concentration to induce 50% cytotoxicity of isolated rat hepatocytes in 2 h and logP as octanol/water partitioning: logLD(50) (microM)=-0.588(+/-0.059)logP+4.652(+/-0.153) (n=27, r(2)=0.801, s=0.261, P<1 x 10(-9)). Hydroquinone, catechol, 4-nitrophenol, and 2,4-dinitrophenol were outliers for this equation. When the ionization constant pK(a) was considered as a contributing factor a two-parameter QSTR equation was derived: logLD(50) (microM)=-0.595(+/-0.051)logP+0.197(+/-0.029)pK(a)+2.665(+/-0.281) (n=28, r(2)=0.859, s=0.218, P<1 x 10(-6)). Using sigma+, the Brown variation of the Hammet electronic constant, as a contributing parameter, the cytotoxicity of phenols towards hepatocytes were defined by logLD(50) (microM)=-0.594(+/-0.052)logP-0.552(+/-0.085)sigma+ +4.540(+/-0.132) (n=28, r(2)=0.853, s=0.223, P<1 x 10(-6)). Replacing sigma+ with the homolytic bond dissociation energy (BDE) for (X-PhOH+PhO.-->X-PhO.+PhOH) led to logLD(50) (microM)=-0.601(+/-0.066)logP-0.040(+/-0.018)BDE+4.611(+/-0.166) (n=23, r(2)=0.827, s=0.223, P<0.05). Hydroquinone, catechol and 2-nitrophenol were outliers for the above equations. Using redox potential and logP led to a new correlation: logLD(50) (microM)=-0.529(+/-0.135)logP+2.077(+/-0.892)E(p/2)+2.806(+/-0.592) (n=15, r(2)=0.561, s=0.383, P<0.05) with 4-nitrophenol as an outlier. Our findings indicate that phenols with higher lipophilicity, BDE, or sigma+ values or with lower pK(a) and redox potential were more toxic towards hepatocytes. We also showed that a collapse of hepatocyte mitochondrial membrane potential preceded the cytotoxicity of most phenols. Our study indicates that one or a combination of mechanisms; i.e. mitochondrial uncoupling, phenoxy radicals, or phenol metabolism to quinone methides and quinones, contribute to phenol cytotoxicity towards hepatocytes depending on the phenol chemical structure.

Radical scavenging activity of lipophilized products from lipase-catalyzed transesterification of triolein with cinnamic and ferulic acids.

PubMed

Choo, Wee-Sim; Birch, Edward John

2009-02-01

Lipase-catalyzed transesterification of triolein with cinnamic and ferulic acids using an immobilized lipase from Candida antarctica (E.C. 3.1.1.3) was conducted to evaluate the antioxidant activity of the lipophilized products as model systems for enhanced protection of unsaturated oil. The lipophilized products were identified using ESI-MS. Free radical scavenging activity was determined using the DPPH radical method. The polarity of the solvents proved important in determining the radical scavenging activity of the substrates. Ferulic acid showed much higher radical scavenging activity than cinnamic acid, which has limited activity. The esterification of cinnamic acid and ferulic acid with triolein resulted in significant increase and decrease in the radical scavenging activity, respectively. These opposite effects were due to the effect of addition of electron-donating alkyl groups on the predominant mechanism of reaction (hydrogen atom transfer or electron transfer) of a species with DPPH. The effect of esterification of cinnamic acid was confirmed using ethyl cinnamate which greatly enhances the radical scavenging activity. Although, compared to the lipophilized cinnamic acid product, the activity was lower. The radical scavenging activity of the main component isolated from lipophilized cinnamic acid product using solid phase extraction, monocinnamoyl dioleoyl glycerol, was as good as the unseparated mixture of lipophilized product. Based on the ratio of a substrate to DPPH concentration, lipophilized ferulic acid was a much more efficient radical scavenger than lipophilized cinnamic acid.

Target-Independent Prediction of Drug Synergies Using Only Drug Lipophilicity

PubMed Central

2015-01-01

Physicochemical properties of compounds have been instrumental in selecting lead compounds with increased drug-likeness. However, the relationship between physicochemical properties of constituent drugs and the tendency to exhibit drug interaction has not been systematically studied. We assembled physicochemical descriptors for a set of antifungal compounds (“drugs”) previously examined for interaction. Analyzing the relationship between molecular weight, lipophilicity, H-bond donor, and H-bond acceptor values for drugs and their propensity to show pairwise antifungal drug synergy, we found that combinations of two lipophilic drugs had a greater tendency to show drug synergy. We developed a more refined decision tree model that successfully predicted drug synergy in stringent cross-validation tests based on only lipophilicity of drugs. Our predictions achieved a precision of 63% and allowed successful prediction for 58% of synergistic drug pairs, suggesting that this phenomenon can extend our understanding for a substantial fraction of synergistic drug interactions. We also generated and analyzed a large-scale synergistic human toxicity network, in which we observed that combinations of lipophilic compounds show a tendency for increased toxicity. Thus, lipophilicity, a simple and easily determined molecular descriptor, is a powerful predictor of drug synergy. It is well established that lipophilic compounds (i) are promiscuous, having many targets in the cell, and (ii) often penetrate into the cell via the cellular membrane by passive diffusion. We discuss the positive relationship between drug lipophilicity and drug synergy in the context of potential drug synergy mechanisms. PMID:25026390

Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study.

PubMed

Shekar, Kiran; Roberts, Jason A; Mcdonald, Charles I; Ghassabian, Sussan; Anstey, Chris; Wallis, Steven C; Mullany, Daniel V; Fung, Yoke L; Fraser, John F

2015-04-14

Vital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits. Four identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24 hours. After baseline sampling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the controls and the ECMO circuits over 24 hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables. Four hundred eighty samples were analysed. There was no significant loss of any study drugs in the controls over 24 hours. The average drug recoveries from the ECMO circuits at 24 hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone (P = 0.01), caspofungin (P = 0.01) and thiopentone (P = 0.008) concentrations in the ECMO circuit at 24 hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination (R (2) = 0.88, P <0.001). Recovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24 hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.

Mitochondrial alkaline pH-responsive drug release mediated by Celastrol loaded glycolipid-like micelles for cancer therapy.

PubMed

Tan, Yanan; Zhu, Yun; Zhao, Yue; Wen, Lijuan; Meng, Tingting; Liu, Xuan; Yang, Xiqin; Dai, Suhuan; Yuan, Hong; Hu, Fuqiang

2018-02-01

Mitochondria, crucial regulators of inducing tumor cells apoptosis, can be treated as the prime target for tumor therapy. The selective and responsive release of proapoptotic therapeutics into mitochondria may notably improve antitumor efficiency. Herein, (4-Carboxybutyl) triphenylphosphonium bromide (CTPP), a lipophilic cation, was conjugated with glucolipid-like conjugates (CSOSA) to produce mitochondria-targeted conjugates (CTPP-CSOSA). Loading with weakly acidic drug Celastrol (Cela), CTPP-CSOSA/Cela micelles could selectively respond to mitochondrial alkaline pH (pH 8.0), controlled by the weaker interaction between hydrophobic core of micelles and Cela with higher solubility at pH 8.0. However, there was a slow drug release behavior at pH 7.4 and pH 5.0. It illustrated that CTPP-CSOSA/Cela could realize mitochondrial fast drug release, and decrease drug leakage in the cytoplasm and lysosome. CTPP-CSOSA/Cela highly enhanced ROS levels, which further induced mitochondria membrane potential decreasing and more Cytochrome C releasing into cytoplasm, then promoted tumor cells apoptosis notably. In vivo, CTPP-CSOSA had an enhanced accumulation in tumor tissue, compared with CSOSA. Moreover, the tumor-inhibition rate of CTPP-CSOSA/Cela was 80.17%, which was significantly higher than CSOSA/Cela (58.35%) and Cela (54.89%). Thus, CTPP-CSOSA/Cela micelles with mitochondrial targeting and alkaline pH-responsive release capability could provide a new strategy for tumor therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis, lipophilicity and antimicrobial activity evaluation of some new thiazolyl-oxadiazolines

PubMed Central

STOICA, CRISTINA IOANA; IONUȚ, IOANA; PÎRNĂU, ADRIAN; POP, CARMEN; ROTAR, ANCUȚA; VLASE, LAURIAN; ONIGA, SMARANDA; ONIGA, OVIDIU

2015-01-01

Background and aims Synthesis of new potential antimicrobial agents and evaluation of their lipophilicity. Methods Ten new thiazolyl-oxadiazoline derivatives were synthesized and their structures were validated by 1H-NMR and mass spectrometry. The lipophilicity of the compounds was evaluated using the principal component analysis (PCA) method. The necessary data for applying this method were obtained by reverse-phase thin-layer chromatography (RP-TLC). The antimicrobial activities were tested in vitro against four bacterial strains and one fungal strain. Results The lipophilicity varied with the structure but could not be correlated with the antimicrobial activity, since this was modest. Conclusions We have synthesized ten new heterocyclic compounds. After their physical and chemical characterization, we determined their lipophilicity and screened their antimicrobial activity. PMID:26733751

Lipophilic components of diesel exhaust particles induce pro-inflammatory responses in human endothelial cells through AhR dependent pathway(s).

PubMed

Brinchmann, Bendik C; Skuland, Tonje; Rambøl, Mia H; Szoke, Krisztina; Brinchmann, Jan E; Gutleb, Arno C; Moschini, Elisa; Kubátová, Alena; Kukowski, Klara; Le Ferrec, Eric; Lagadic-Gossmann, Dominique; Schwarze, Per E; Låg, Marit; Refsnes, Magne; Øvrevik, Johan; Holme, Jørn A

2018-05-11

Exposure to traffic-derived particulate matter (PM), such as diesel exhaust particles (DEP), is a leading environmental cause of cardiovascular disease (CVD), and may contribute to endothelial dysfunction and development of atherosclerosis. It is still debated how DEP and other inhaled PM can contribute to CVD. However, organic chemicals (OC) adhered to the particle surface, are considered central to many of the biological effects. In the present study, we have explored the ability of OC from DEP to reach the endothelium and trigger pro-inflammatory reactions, a central step on the path to atherosclerosis. Exposure-relevant concentrations of DEP (0.12 μg/cm 2 ) applied on the epithelial side of an alveolar 3D tri-culture, rapidly induced pro-inflammatory and aryl hydrocarbon receptor (AhR)-regulated genes in the basolateral endothelial cells. These effects seem to be due to soluble lipophilic constituents rather than particle translocation. Extractable organic material of DEP (DEP-EOM) was next fractionated with increasing polarity, chemically characterized, and examined for direct effects on pro-inflammatory and AhR-regulated genes in human microvascular endothelial (HMEC-1) cells and primary human endothelial cells (PHEC) from four healthy donors. Exposure-relevant concentrations of lipophilic DEP-EOM (0.15 μg/cm 2 ) induced low to moderate increases in IL-1α, IL-1β, COX2 and MMP-1 gene expression, and the MMP-1 secretion was increased. By contrast, the more polar EOM had negligible effects, even at higher concentrations. Use of pharmacological inhibitors indicated that AhR and protease-activated receptor-2 (PAR-2) were central in regulation of EOM-induced gene expression. Some effects also seemed to be attributed to redox-responses, at least at the highest exposure concentrations tested. Although the most lipophilic EOM, that contained the majority of PAHs and aliphatics, had the clearest low-concentration effects, there was no straight-forward link between chemical composition and biological effects. Lipophilic and semi-lipophilic chemicals seemed to detach from DEP, translocate through alveolar epithelial cells and trigger pro-inflammatory reactions in endothelial cells at exposure-relevant concentrations. These effects appeared to be triggered by AhR agonists, and involve PAR-2 signaling.

Multiple sclerosis: evaluation of purine nucleotide metabolism in central nervous system in association with serum levels of selected fat-soluble antioxidants.

PubMed

Kuračka, Lubomír; Kalnovičová, Terézia; Kucharská, Jarmila; Turčáni, Peter

2014-01-01

In the pathogenesis of demyelinating diseases including multiple sclerosis (MS) an important role is played by oxidative stress. Increased energy requirements during remyelination of axons and mitochondria failure is one of the causes of axonal degeneration and disability in MS. In this context, we analyzed to what extent the increase in purine catabolism is associated with selected blood lipophilic antioxidants and if there is any association with alterations in serum levels of coenzyme Q10. Blood serum and cerebrospinal fluid (CSF) samples from 42 patients with diagnosed MS and 34 noninflammatory neurologic patients (control group) were analyzed. Compared to control group, MS patients had significantly elevated values of all purine nucleotide metabolites, except adenosine. Serum lipophilic antioxidants γ -tocopherol, β -carotene, and coenzyme Q10 for the vast majority of MS patients were deficient or moved within the border of lower physiological values. Serum levels of TBARS, marker of lipid peroxidation, were increased by 81% in the MS patients. The results indicate that the deficit of lipophilic antioxidants in blood of MS patients may have a negative impact on bioenergetics of reparative remyelinating processes and promote neurodegeneration.

In Silico Study of Chromatographic Lipophilicity Parameters of 3-(4-Substituted Benzyl)-5-Phenylhydantoins.

PubMed

Sekulic, Tatjana Djakovic; Keleman, Svetlana; Tot, Kristina; Tot, Jadranka; Trisovic, Nemanja; Uscumlic, Gordana

2016-01-01

New synthesized compounds, particularly those with biological activity, are potential drug candidates. This article describes experimental studies performed to estimate lipophilicity parameters of new 3-(4-substituted benzyl)-5-phenylhydantoins. Lipophilicity, as one of the most important molecular characteristics for the activity, was determined using the reversed-phase liquid chromatography (RP-18 stationary phase and methanol-water mobile phase). Molecular structures were used to generate in silico data which were used to estimate pharmacokinetic properties of the investigated compounds. The results show that generally, the investigated compounds attain good bioavailability properties. A more detailed analysis shows that the presence of a nitro, methoxy and tert-butyl group in the molecule is indicated as unfavorable for the oral bioavailability of hydantoins. Multivariate exploratory analysis was used in order to visualize grouping patterns among molecular descriptors as well as among the investigated compounds. Molecular docking study performed for two hydantoins with the highest bioavailability scores shows high binding affinity to tyrosine kinase receptor IGF-1R. The results achieved can be useful as a template for future development and further derivation or modification to obtain more potent and selective antitumor agents.

Antimicrobial activity and self-assembly behavior of antimicrobial peptide chensinin-1b with lipophilic alkyl tails.

PubMed

Dong, Weibing; Liu, Ziang; Sun, Liying; Wang, Cui; Guan, Yue; Mao, Xiaoman; Shang, Dejing

2018-04-25

The threshold hydrophobicity and amphipathic structure of the peptidic chain are important for the biological function of antimicrobial peptides. Chensinin-1b exhibits broad-spectrum bactericidal activity with no hemolytic activity but has almost no anticancer ability against the selected cancer cell lines. In this study, the conjugation of aliphatic acid was designed with different lengths of N-terminal of chensinin-1b, the antimicrobial activity of the resulting lipo-chensinin-1b was examined, in which OA-C1b showed much stronger activity than those of cheninin-1b and the other two lipopeptides. The membrane interaction between the lipo-chensinin-1b and real/mimetic bacterial cell membrane was investigated. Electrostatic interactions between the lipo-chensinin-1b and lipopolysaccharides were detected by isothermal titration calorimetry and the binding affinities were 10.83 μM, 8.77 μM and 7.35 μM for OA-C1b, LA-C1b and PA-C1b, respectively. The antimicrobial activity and membrane interaction ability of the lipo-chensinin-1b followed this order: OA-C1b > chensinin-1b > LA-C1b > PA-C1b. In addition, the lipo-chensinin-1b also exhibited lytic activity against various cancer cells and demonstrated the ability to inhibit LPS-stimulated cytokine release from human U937 cells. The CD spectra indicated that the helical or β-strands contents were existed as the main components in TFE or LPS solution, respectively. The self-assembly behavior was trigged by the solution pH and affected by the length of carbon chain, in which chensinin-1b, OA-C1b, LA-C1b and PA-C1b formed micelles at neutral pH and the micelle size increased for chensinin-1b, OA-C1b and LA-C1b. PA-C1b formed nanofibers in an acidic environment indicated by TEM experiments, and the peptides formed aggregates in an acidic environment and re-dissociated when the pH was adjusted to neutral. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Preformulation experiences and in vitro model studies with spironolactone-containing suppositories.

PubMed

Regdon, G; Deák, D; Regdon, G; Muskó, Z; Erös, I

2001-01-01

The optimal suppository base for the formulation of rectal suppositories containing diuretic spironolactone was selected experimentally. Model studies were carried out about the effect of solubility-increasing additives on the release of the drug from the suppositories. During the in vitro examinations acceptor phases of different pH values were used, and both diffusion time and the number of samplings were changed. Among the lipophilic and hydrophilic suppository bases studied the hydrophilic Macrogolum 1540 was found to be optimal. The release and diffusion of spironolactone was the most favourable from these suppositories. During storage these suppositories remained stable and the values of release did not decrease significantly (p < 0.05).

Nanostructured lipid carrier-loaded hyaluronic acid microneedles for controlled dermal delivery of a lipophilic molecule

PubMed Central

Lee, Sang Gon; Jeong, Jae Han; Lee, Kyung Min; Jeong, Kyu Ho; Yang, Huisuk; Kim, Miroo; Jung, Hyungil; Lee, Sangkil; Choi, Young Wook

2014-01-01

Nanostructured lipid carriers (NLCs) were employed to formulate a lipophilic drug into hydrophilic polymeric microneedles (MNs). Hyaluronic acid (HA) was selected as a hydrophilic and bioerodible polymer to fabricate MNs, and nile red (NR) was used as a model lipophilic molecule. NR-loaded NLCs were consolidated into the HA-based MNs to prepare NLC-loaded MNs (NLC-MNs). A dispersion of NLCs was prepared by high-pressure homogenization after dissolving NR in Labrafil and mixing with melted Compritol, resulting in 268 nm NLCs with a polydispersity index of 0.273. The NLC dispersion showed a controlled release of NR over 24 hours, following Hixson–Crowell’s cube root law. After mixing the NLC dispersion with the HA solution, the drawing lithography method was used to fabricate NLC-MNs. The length, base diameter, and tip diameter of the NLC-MNs were approximately 350, 380, and 30 μm, respectively. Fluorescence microscopic imaging of the NLC-MNs helped confirm that the NR-loaded NLCs were distributed evenly throughout the MNs. In a skin permeation study performed using a Franz diffusion cell with minipig dorsal skin, approximately 70% of NR was localized in the skin after 24-hour application of NLC-MNs. Confocal laser scanning microscopy (z-series) of the skin at different depths showed strong fluorescence intensity in the epidermal layer, which appeared to spread out radially with the passage of time. This study indicated that incorporation of drug-loaded NLCs into MNs could represent a promising strategy for controlled dermal delivery of lipophilic drugs. PMID:24403833

Effect of O-acylmenthol on transdermal delivery of drugs with different lipophilicity.

PubMed

Zhao, Ligang; Fang, Liang; Xu, Yongnan; Zhao, Yanyan; He, Zhonggui

2008-03-20

To develop more effective compounds as enhancers, O-acylmenthol derivatives which were expected to be enzymatically hydrolyzed into nontoxic metabolites by esterases in the living epidermis were synthesized from l-menthol and pharmaceutical excipient acids (lactic acid, cinnamic acid, salicylic acid and oleic acid) in this study. Their promoting activity on the percutaneous absorption of five model drugs, 5-fluorouracil (5-FU), isosorbide dinitrate (ISDN), lidocaine (LD), ketoprofen (KP), and indomethacin (IM), which were selected based on their lipophilicity represented by log K(O/W), were tested in vitro across full thickness rat skin with each of the evaluated drugs in saturated donor solution. 2-Isopropyl-5-methylcyclohexyl 2-hydroxypanoate (M-LA) provided the highest increase of accumulation of 5-FU (3.74-fold) and LD (4.19-fold) in the receptor phase while 2-isopropyl-5-methylcyclohexyl cinnamate (M-CA) was ineffective for most of the drugs; Both 2-isopropyl-5-methylcyclohexyl 2-hydroxybenzoate (M-SA) and (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate (M-OA) had better promoting effects on the drugs with low water-solubility. The four O-acylmenthol enhancers produced parabolic relationship between the lipophilicity (log K(O/W)) of the model drugs (5-FU, ISDN, KP, IM) and their enhancement ratio of the permeation coefficient (ER(P)), indicating that the lipophilicity of the penetrants has significant effect on the permeation results, r = 0.989 (P=0.144) for M-LA, r = 0.965 (P = 0.216) for M-CA, r = 0.786 (P = 0.630) for M-SA, and r = 0.996 (P = 0.088) for M-OA.

Penetration studies of an extremely lipophilic active model substance from an oil-in-water emulsion: influence of the lipophilicity of the formulation in human skin - part 2.

PubMed

Naumann, S; Lange, S; Polak, G; Kalhoelfer, V; Motlagh, L; Goebel, A; Wohlrab, J; Neubert, R H H

2014-01-01

The effect of the lipophilicity of a carrier on human skin penetration of an extremely lipophilic active model substance was evaluated by using Franz type diffusion cells. Oil-in-water model emulsions containing different amounts of the oily phase were prepared, and Myritol® PC (M-PC) was selected as lipophilic marker component of the oily phase. The penetrated amounts of the lipophilic model substance salicyloyl phytosphingosine (SP) were determined by high-performance liquid chromatography with ultraviolet detection, while M-PC was detected using gas chromatography coupled with mass spectrometry. It has been ascertained that the amount of the lipid phase within the emulsion influenced the penetration profile of the active ingredient SP. The emulsion containing the lowest proportion of the lipid phase provides the best conditions for SP penetration. Surprisingly, the penetration behavior of M-PC was influenced by the oily phase in the same way. Regarding the M-PC and the SP penetration profiles from each emulsion, a solvent drag mechanism can be assumed whereby M-PC acts as penetration enhancer. In conclusion, the penetration rate of the active ingredient SP and the marker component M-PC are in reverse proportion to the oil content of the formulations. The lipophilicity of SP and M-PC, their solubility and their thermodynamic activity within the vehicle could have an effect on their penetration behavior. Additionally, M-PC has the property to enhance the penetration rates of extremely lipophilic substances even at low concentrations.

Enzymatic lipophilization of epicatechin with free fatty acids and its effect on antioxidative capacity in crude camellia seed oil.

PubMed

Chen, Sa-Sa; Luo, Shui-Zhong; Zheng, Zhi; Zhao, Yan-Yan; Pang, Min; Jiang, Shao-Tong

2017-02-01

Crude camellia seed oil is rich in free fatty acids, which must be removed to produce an oil of acceptable quality. In the present study, we reduced the free fatty acid content of crude camellia seed oil by lipophilization of epicatechin with these free fatty acids in the presence of Candida antarctica lipase B (Novozym 435), and this may enhance the oxidative stability of the oil at the same time. The acid value of crude camellia seed oil reduced from 3.7 to 2.5 mgKOH g -1 after lipophilization. Gas chomatography-mass spectrometry analysis revealed that epicatechin oleate and epicatechin palmitate were synthesized in the lipophilized oil. The peroxide, p-anisidine, and total oxidation values during heating of the lipophilized oil were much lower than that of the crude oil and commercially available camellia seed oil, suggesting that lipophilized epicatechin derivatives could help enhance the oxidative stability of edible oil. The enzymatic process to lipophilize epicatechin with the free fatty acids in crude camellia seed oil described in the present study could decrease the acid value to meet the quality standards for commercial camellia seed oil and, at the same time, obtain a new edible camellia seed oil product with good oxidative stability. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

The effect of oral castor oil on the disposition of methyprylon in intoxicated dogs.

PubMed

Gwilt, P R; Pankaskie, M C; Mitala, J J

1982-07-01

Clinical observations indicate that large oral doses of castor oil are effective in reducing the time of coma resulting from acute intoxication with lipophilic drugs. It has been further suggested that the rate of removal of these drugs from the body is increased by castor oil. In order to investigate the effect of castor oil on the disposition of lipophilic drugs, five dogs were given toxic doses of methyprylon by intravenous infusion. Each dog was treated with a large oral dose of castor oil in a cross-over fashion. No significant difference was observed in the sleep times of the dogs treated with castor oil, or in the methyprylon pharmacokinetics compared to controls. It was concluded that castor oil does not affect the disposition of methyprylon.

Estimation hydrophilic-lipophilic balance number of surfactants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pawignya, Harsa, E-mail: harsa-paw@yahoo.co.id; Chemical Engineering Departement University of Pembangunan Nasional Yogyakarta; Prasetyaningrum, Aji, E-mail: ajiprasetyaningrum@gmail.com

Any type of surfactant has a hydrophilic-lipophilic balance number (HLB number) of different. There are several methods for determining the HLB number, with ohysical properties of surfactant (solubility cloud point and interfacial tension), CMC methods and by thermodynamics properties (Free energy Gibbs). This paper proposes to determined HLB numbers from interfelation methods. The result of study indicated that the CMC method described by Hair and Moulik espesially for nonionic surfactant. The application of exess Gibbs free energy and by implication activity coefficient provides the ability to predict the behavior of surfactants in multi component mixtures of different concentration. Determination ofmore » HLB number by solubility and cloud point parameter is spesific for anionic and nonionic surfactant but this methods not available for cationic surfactants.« less

Organoboron compounds as Lewis acid receptors of fluoride ions in polymeric membranes.

PubMed

Jańczyk, Martyna; Adamczyk-Woźniak, Agnieszka; Sporzyński, Andrzej; Wróblewski, Wojciech

2012-07-06

Newly synthesized organoboron compounds - 4-octyloxyphenylboronic acid (OPBA) and pinacol ester of 2,4,6-trifluorophenylboronic acid (PE-PBA) - were applied as Lewis acid receptors of fluoride anions. Despite enhanced selectivity, the polymer membrane electrodes containing the lipophilic receptor OPBA exhibited non-Nernstian slopes of the responses toward fluoride ions in acidic conditions. Such behavior was explained by the lability of the B-O bond in the boronic acids, and the OH(-)/F(-) exchange at higher fluoride content in the sample solution. In consequence, the stoichiometry of the OPBA-fluoride complexes in the membrane could vary during the calibration, changing the equilibrium concentration of the primary anion in membrane and providing super-Nernstian responses. The proposed mechanism was supported by (19)F NMR studies, which indicated that the fluoride complexation proceeds more effectively in acidic solution leading mainly to PhBF(3)(-) species. Finally, the performances of the membranes based on the phenylboronic acid pinacol ester, with a more stable B-O bond, were tested. As it was expected, Nernstian fluoride responses were recorded for such membranes with worsened fluoride selectivity. Copyright © 2012 Elsevier B.V. All rights reserved.

Roles of affinity and lipophilicity in the slow kinetics of prostanoid receptor antagonists on isolated smooth muscle preparations

PubMed Central

Jones, RL; Woodward, DF; Wang, JW; Clark, RL

2011-01-01

BACKGROUND AND PURPOSE The highly lipophilic acyl-sulphonamides L-798106 and L-826266 showed surprisingly slow antagonism of the prostanoid EP3 receptor system in guinea-pig aorta. Roles of affinity and lipophilicity in the onset kinetics of these and other prostanoid ligands were investigated. EXPERIMENTAL APPROACH Antagonist selectivity was assessed using a panel of human recombinant prostanoid receptor-fluorimetric imaging plate reader assays. Potencies/affinities and onset half-times of agonists and antagonists were obtained on guinea-pig-isolated aorta and vas deferens. n-Octanol-water partition coefficients were predicted. KEY RESULTS L-798106, L-826266 and the less lipophilic congener (DG)-3ap appear to behave as selective, competitive-reversible EP3 antagonists. For ligands of low to moderate lipophilicity, potency increments for EP3 and TP (thromboxane-like) agonism on guinea-pig aorta (above pEC50 of 8.0) were associated with progressively longer onset half-times; similar trends were found for TP and histamine H1 antagonism above a pA2 limit of 8.0. In contrast, L-798106 (EP3), L-826266 (EP3, TP) and the lipophilic H1 antagonists astemizole and terfenadine exhibited very slow onset rates despite their moderate affinities; (DG)-3ap (EP3) had a faster onset. Agonism and antagonism on the vas deferens EP3 system were overall much faster, although trends were similar. CONCLUSIONS AND IMPLICATIONS High affinity and high liphophilicity may contribute to the slow onsets of prostanoid ligands in some isolated smooth muscle preparations. Both relationships are explicable by tissue disposition under the limited diffusion model. EP3 antagonists used as research tools should have moderate lipophilicity. The influence of lipophilicity on the potential clinical use of EP3 antagonists is discussed. PMID:20973775

Graphene-based biomimetic materials targeting urine metabolite as potential cancer biomarker: application over different conductive materials for potentiometric transduction.

PubMed

Truta, Liliana A A N A; Ferreira, Nádia S; Sales, M Goreti F

2014-12-20

This works presents a novel surface Smart Polymer Antibody Material (SPAM) for Carnitine (CRT, a potential biomarker of ovarian cancer), tested for the first time as ionophore in potentiometric electrodes of unconventional configuration. The SPAM material consisted of a 3D polymeric network created by surface imprinting on graphene layers. The polymer was obtained by radical polymerization of (vinylbenzyl)trimethylammonium chloride and 4-styrenesulfonic acid (signaling the binding sites), and vinyl pivalate and ethylene glycol dimethacrylate (surroundings). Non-imprinted material (NIM) was prepared as control, by excluding the template from the procedure. These materials were then used to produce several plasticized PVC membranes, testing the relevance of including the SPAM as ionophore, and the need for a charged lipophilic additive. The membranes were casted over solid conductive supports of graphite or ITO/FTO. The effect of pH upon the potentiometric response was evaluated for different pHs (2-9) with different buffer compositions. Overall, the best performance was achieved for membranes with SPAM ionophore, having a cationic lipophilic additive and tested in HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer, pH 5.1. Better slopes were achieved when the membrane was casted on conductive glass (-57.4mV/decade), while the best detection limits were obtained for graphite-based conductive supports (3.6×10 -5 mol/L). Good selectivity was observed against BSA, ascorbic acid, glucose, creatinine and urea, tested for concentrations up to their normal physiologic levels in urine. The application of the devices to the analysis of spiked samples showed recoveries ranging from 91% (± 6.8%) to 118% (± 11.2%). Overall, the combination of the SPAM sensory material with a suitable selective membrane composition and electrode design has lead to a promising tool for point-of-care applications.

Graphene-based biomimetic materials targeting urine metabolite as potential cancer biomarker: application over different conductive materials for potentiometric transduction

PubMed Central

Truta, Liliana A.A.N.A.; Ferreira, Nádia S.; Sales, M. Goreti F.

2015-01-01

This works presents a novel surface Smart Polymer Antibody Material (SPAM) for Carnitine (CRT, a potential biomarker of ovarian cancer), tested for the first time as ionophore in potentiometric electrodes of unconventional configuration. The SPAM material consisted of a 3D polymeric network created by surface imprinting on graphene layers. The polymer was obtained by radical polymerization of (vinylbenzyl)trimethylammonium chloride and 4-styrenesulfonic acid (signaling the binding sites), and vinyl pivalate and ethylene glycol dimethacrylate (surroundings). Non-imprinted material (NIM) was prepared as control, by excluding the template from the procedure. These materials were then used to produce several plasticized PVC membranes, testing the relevance of including the SPAM as ionophore, and the need for a charged lipophilic additive. The membranes were casted over solid conductive supports of graphite or ITO/FTO. The effect of pH upon the potentiometric response was evaluated for different pHs (2-9) with different buffer compositions. Overall, the best performance was achieved for membranes with SPAM ionophore, having a cationic lipophilic additive and tested in HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer, pH 5.1. Better slopes were achieved when the membrane was casted on conductive glass (−57.4mV/decade), while the best detection limits were obtained for graphite-based conductive supports (3.6×10−5mol/L). Good selectivity was observed against BSA, ascorbic acid, glucose, creatinine and urea, tested for concentrations up to their normal physiologic levels in urine. The application of the devices to the analysis of spiked samples showed recoveries ranging from 91% (± 6.8%) to 118% (± 11.2%). Overall, the combination of the SPAM sensory material with a suitable selective membrane composition and electrode design has lead to a promising tool for point-of-care applications. PMID:26456975

Free fatty acids electronically bridge the self-assembly of a three-component nanocomplex consisting of amylose, protein, and free fatty acids.

PubMed

Zhang, Genyi; Maladen, Michelle; Campanella, Osvaldo H; Hamaker, Bruce R

2010-08-25

The self-assembly of a ternary complex, which is formed through heating and cooling of a mixture of amylose (1.0 mg/mL), whey protein isolate (50 μg/mL), and free fatty acids (FFAs, 250 μg/mL) was investigated. High-performance size-exclusion chromatography-multi-angle laser light scattering (HPSEC-MALLS) analysis showed that the complex is a water-soluble supramolecule (Mw = 6-7 × 10(6)), with a radius of gyration of 20-100 nm, indicating a nanoscale complex. Experimental results using 1-monostearyl-rac-glycerol (MSG) or cetyl alcohol that is similar to FFA in structure (except the headgroup) indicate that FFAs are the bridge between thermodynamically incompatible amylose and protein molecules and their functional carboxyl group is essential to the formation of the complex. Additionally, the effects of pH and salt treatments suggest that electrostatic interactions between negatively charged carboxyl groups of FFAs and polyionic protein are the foundation for the self-assembly of the complex. The fact that FFA is one important component in the self-assembled complex with an estimated molar ratio of 6:1:192 (amylose/protein/FFA, ∼4-5% FFA) demonstrates that it might be used as a nanocarrier for the controlled release of lipophilic functional materials to maintain their stability, bioactivity, and more importantly water solubility.

High lipophilicity of meta Mn(III) N-alkylpyridylporphyrin-based SOD mimics compensates for their lower antioxidant potency and makes them equally effective as ortho analogues in protecting SOD-deficient E. coli

PubMed Central

Kos, Ivan; Benov, Ludmil; Spasojević, Ivan; Rebouças, Júlio S.; Batinić-Haberle, Ines

2009-01-01

Lipophilicity/bioavailibility of Mn(III)N-alkylpyridylporphyrin-based SOD mimics has major impact on their in vivo ability to suppress oxidative stress. Meta isomers are less potent SOD mimics than ortho analogues, but are 10-fold more lipophilic and more planar. Enhanced lipophilicity contributes to their higher accumulation in cytosol of SOD-deficient E. coli, compensating for their lower potency; consequently both isomers exert similar-to-identical protection of SOD-deficient E. coli. Thus meta isomers may be as prospective therapeutics as are ortho porphyrins. PMID:19954250

Lipophilic oligonucleotides spontaneously insert into lipid membranes, bind complementary DNA strands, and sequester into lipid-disordered domains.

PubMed

Bunge, Andreas; Kurz, Anke; Windeck, Anne-Kathrin; Korte, Thomas; Flasche, Wolfgang; Liebscher, Jürgen; Herrmann, Andreas; Huster, Daniel

2007-04-10

For the development of surface functionalized bilayers, we have synthesized lipophilic oligonucleotides to combine the molecular recognition mechanism of nucleic acids and the self-assembly characteristics of lipids in planar membranes. A lipophilic oligonucleotide consisting of 21 thymidine units and two lipophilic nucleotides with an alpha-tocopherol moiety as a lipophilic anchor was synthesized using solid-phase methods with a phosphoramadite strategy. The interaction of the water soluble lipophilic oligonucleotide with vesicular lipid membranes and its capability to bind complementary DNA strands was studied using complementary methods such as NMR, EPR, DSC, fluorescence spectroscopy, and fluorescence microscopy. This oligonucleotide inserted stably into preformed membranes from the aqueous phase. Thereby, no significant perturbation of the lipid bilayer and its stability was observed. However, the non-lipidated end of the oligonucleotide is exposed to the aqueous environment, is relatively mobile, and is free to interact with complementary DNA strands. Binding of the complementary single-stranded DNA molecules is fast and accomplished by the formation of Watson-Crick base pairs, which was confirmed by 1H NMR chemical shift analysis and fluorescence resonance energy transfer. The molecular structure of the membrane bound DNA double helix is very similar to the free double-stranded DNA. Further, the membrane bound DNA double strands also undergo regular melting. Finally, in raft-like membrane mixtures, the lipophilic oligonucleotide was shown to preferentially sequester into liquid-disordered membrane domains.

Determination of the effect of lipophilicity on the in vitro permeability and tissue reservoir characteristics of topically applied solutes in human skin layers.

PubMed

Cross, Sheree E; Magnusson, Beatrice M; Winckle, Gareth; Anissimov, Yuri; Roberts, Michael S

2003-05-01

In order to establish the relationship between solute lipophilicity and skin penetration (including flux and concentration behavior), we examined the in vitro penetration and membrane concentration of a series of homologous alcohols (C2-C10) applied topically in aqueous solutions to human epidermal, full-thickness, and dermal membranes. The partitioning/distribution of each alcohol between the donor solution, stratum corneum, viable epidermis, dermis, and receptor phase compartments was determined during the penetration process and separately to isolated samples of each tissue type. Maximum flux and permeability coefficients are compared for each membrane and estimates of alcohol diffusivity are made based on flux/concentration data and also the related tissue resistance (the reciprocal of permeability coefficient) for each membrane type. The permeability coefficient increased with increasing lipophilicity to alcohol C8 (octanol) with no further increase for C10 (decanol). Log vehicle:stratum corneum partition coefficients were related to logP, and the concentration of alcohols in each of the tissue layers appeared to increase with lipophilicity. No difference was measured in the diffusivity of smaller more polar alcohols in the three membranes; however, the larger more lipophilic solutes showed slower diffusivity values. The study showed that the dermis may be a much more lipophilic environment than originally believed and that distribution of smaller nonionized solutes into local tissues below a site of topical application may be estimated based on knowledge of their lipophilicity alone.

Vacuolar H+-ATPase Protects Saccharomyces cerevisiae Cells against Ethanol-Induced Oxidative and Cell Wall Stresses

PubMed Central

Charoenbhakdi, Sirikarn; Dokpikul, Thanittra; Burphan, Thanawat; Techo, Todsapol

2016-01-01

ABSTRACT During fermentation, increased ethanol concentration is a major stress for yeast cells. Vacuolar H+-ATPase (V-ATPase), which plays an important role in the maintenance of intracellular pH homeostasis through vacuolar acidification, has been shown to be required for tolerance to straight-chain alcohols, including ethanol. Since ethanol is known to increase membrane permeability to protons, which then promotes intracellular acidification, it is possible that the V-ATPase is required for recovery from alcohol-induced intracellular acidification. In this study, we show that the effects of straight-chain alcohols on membrane permeabilization and acidification of the cytosol and vacuole are strongly dependent on their lipophilicity. These findings suggest that the membrane-permeabilizing effect of straight-chain alcohols induces cytosolic and vacuolar acidification in a lipophilicity-dependent manner. Surprisingly, after ethanol challenge, the cytosolic pH in Δvma2 and Δvma3 mutants lacking V-ATPase activity was similar to that of the wild-type strain. It is therefore unlikely that the ethanol-sensitive phenotype of vma mutants resulted from severe cytosolic acidification. Interestingly, the vma mutants exposed to ethanol exhibited a delay in cell wall remodeling and a significant increase in intracellular reactive oxygen species (ROS). These findings suggest a role for V-ATPase in the regulation of the cell wall stress response and the prevention of endogenous oxidative stress in response to ethanol. IMPORTANCE The yeast Saccharomyces cerevisiae has been widely used in the alcoholic fermentation industry. Among the environmental stresses that yeast cells encounter during the process of alcoholic fermentation, ethanol is a major stress factor that inhibits yeast growth and viability, eventually leading to fermentation arrest. This study provides evidence for the molecular mechanisms of ethanol tolerance, which is a desirable characteristic for yeast strains used in alcoholic fermentation. The results revealed that straight-chain alcohols induced cytosolic and vacuolar acidification through their membrane-permeabilizing effects. Contrary to expectations, a role for V-ATPase in the regulation of the cell wall stress response and the prevention of endogenous oxidative stress, but not in the maintenance of intracellular pH, seems to be important for protecting yeast cells against ethanol stress. These findings will expand our understanding of the mechanisms of ethanol tolerance and provide promising clues for the development of ethanol-tolerant yeast strains. PMID:26994074

Vacuolar H+-ATPase Protects Saccharomyces cerevisiae Cells against Ethanol-Induced Oxidative and Cell Wall Stresses.

PubMed

Charoenbhakdi, Sirikarn; Dokpikul, Thanittra; Burphan, Thanawat; Techo, Todsapol; Auesukaree, Choowong

2016-05-15

During fermentation, increased ethanol concentration is a major stress for yeast cells. Vacuolar H(+)-ATPase (V-ATPase), which plays an important role in the maintenance of intracellular pH homeostasis through vacuolar acidification, has been shown to be required for tolerance to straight-chain alcohols, including ethanol. Since ethanol is known to increase membrane permeability to protons, which then promotes intracellular acidification, it is possible that the V-ATPase is required for recovery from alcohol-induced intracellular acidification. In this study, we show that the effects of straight-chain alcohols on membrane permeabilization and acidification of the cytosol and vacuole are strongly dependent on their lipophilicity. These findings suggest that the membrane-permeabilizing effect of straight-chain alcohols induces cytosolic and vacuolar acidification in a lipophilicity-dependent manner. Surprisingly, after ethanol challenge, the cytosolic pH in Δvma2 and Δvma3 mutants lacking V-ATPase activity was similar to that of the wild-type strain. It is therefore unlikely that the ethanol-sensitive phenotype of vma mutants resulted from severe cytosolic acidification. Interestingly, the vma mutants exposed to ethanol exhibited a delay in cell wall remodeling and a significant increase in intracellular reactive oxygen species (ROS). These findings suggest a role for V-ATPase in the regulation of the cell wall stress response and the prevention of endogenous oxidative stress in response to ethanol. The yeast Saccharomyces cerevisiae has been widely used in the alcoholic fermentation industry. Among the environmental stresses that yeast cells encounter during the process of alcoholic fermentation, ethanol is a major stress factor that inhibits yeast growth and viability, eventually leading to fermentation arrest. This study provides evidence for the molecular mechanisms of ethanol tolerance, which is a desirable characteristic for yeast strains used in alcoholic fermentation. The results revealed that straight-chain alcohols induced cytosolic and vacuolar acidification through their membrane-permeabilizing effects. Contrary to expectations, a role for V-ATPase in the regulation of the cell wall stress response and the prevention of endogenous oxidative stress, but not in the maintenance of intracellular pH, seems to be important for protecting yeast cells against ethanol stress. These findings will expand our understanding of the mechanisms of ethanol tolerance and provide promising clues for the development of ethanol-tolerant yeast strains. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Pyridinedicarboxylates, the first mechanism-derived inhibitors for prolyl 4-hydroxylase, selectively suppress cellular hydroxyprolyl biosynthesis. Decrease in interstitial collagen and Clq secretion in cell culture.

PubMed Central

Tschank, G; Raghunath, M; Günzler, V; Hanauske-Abel, H M

1987-01-01

Two pyridinedicarboxylates, predicted [Hanauske-Abel (1983) M.D.-Ph.D. Thesis, Philipps Universität Marburg] and later found to be potent reversible inhibitors of purified prolyl 4-hydroxylase [Majaama, Hanauske-Abel, Günzler & Kivirikko (1984) Eur. J. Biochem. 138, 239-245] were investigated with respect to their effect on hydroxyprolyl biosynthesis in the fibroblast/collagen and the macrophage/Clq systems, and the effect was compared with that of the iron chelator 2,2'-dipyridyl, the compound usually employed to inhibit cellular hydroxyprolyl formation. Only the enzyme-mechanism-derived pyridinedicarboxylates were highly selective inhibitors, and only they lacked overt cytotoxicity. Morphologically, their effect was restricted to the site of cellular hydroxyprolyl biosynthesis, i.e. the cisternae of the rough-surfaced endoplasmic reticulum. They were equally effective in the different cell types studied, and human and guinea-pig fibroblasts showed the same sensitivity. The minimal lipophilicity of the pyridinedicarboxylates necessitated high concentrations to achieve suppression of cellular hydroxyprolyl formation, but lipophilic bio-activatable pro-inhibitors may overcome this disadvantage. For the first time, experimental evidence is presented suggesting that, in cell culture, the biosynthesis of interstitial collagens and Clq can be suppressed selectively, identifying the pyridinedicarboxylates as promising pilot compounds for experiments in vivo. Images Fig. 3. Fig. 4. PMID:2829835

Propranolol transport across the inner blood-retinal barrier: potential involvement of a novel organic cation transporter.

PubMed

Kubo, Yoshiyuki; Shimizu, Yoshimi; Kusagawa, Yusuke; Akanuma, Shin-Ichi; Hosoya, Ken-Ichi

2013-09-01

The influx transport of propranolol across the inner blood-retinal barrier (BRB) was investigated. In the in vivo analysis of carotid artery single-injection method, [(3) H]propranolol uptake by the retina was greater than that of an internal reference compound, and was reduced by several organic cations. In the in vitro uptake study, TR-iBRB2 cells, an in vitro model of the inner BRB, showed a time-, concentration-, pH- and temperature-dependent [(3) H]propranolol uptake, suggesting the involvement of a carrier-mediated transport process in the influx of propranolol across the inner BRB. In the inhibition study, various organic cations, including drugs and candidates for the treatment of the retinal diseases, inhibited the [(3) H]propranolol uptake by TR-iBRB2 cells with no significant effects by the substrates and inhibitors of well-characterized organic cation transporters, suggesting that the influx transport of propranolol is performed by a novel transporter at the inner BRB. An analysis of the relationship between the inhibitory effect and the lipophilicity of inhibitors suggests a lipophilicity-dependent inhibitory effect of amines on the [(3) H]propranolol uptake by TR-iBRB2 cells. These results showed that influx transport of propranolol across the inner BRB is performed by a carrier-mediated transport process, suggesting the involvement of a novel organic cation transporter. Copyright © 2013 Wiley Periodicals, Inc.

Retention of bile salts in micellar electrokinetic chromatography: relation of capacity factor to octanol-water partition coefficient and critical micellar concentration.

PubMed

Lucangioli, S E; Carducci, C N; Tripodi, V P; Kenndler, E

2001-12-25

The capacity factors of 16 anionic cholates (from six bile salts, including their glyco- and tauro-conjugates) were determined in a micellar electrokinetic chromatography (MEKC) system consisting of buffer, pH 7.5 (phosphate-boric acid; 20 mmol/l) with 50 mmol/l sodium dodecyl sulfate (SDS) as micelle former and 10% acetonitrile as organic modifier. The capacity factors of the fully dissociated, negatively charged analytes (ranging between 0.2 and 60) were calculated from their mobilities, with a reference background electrolyte (BGE) without SDS representing "free" solution. For comparison, the capacity factors were derived for a second reference BGE where the SDS concentration (5 mmol/l) is close to the critical micellar concentration (CMC). The capacity factors are compared with the logarithm of the octanol-water partition coefficient, log Pow, as measure for lipophilicity. Clear disagreement between these two parameters is found especially for epimeric cholates with the hydroxy group in position 7. In contrast, fair relation between the capacity factor of the analytes and their CMC is observed both depending strongly on the orientation of the OH groups, and tauro-conjugation as well. In this respect the retention behaviour of the bile salts in MEKC seems to reflect their role as detergents in living systems, and might serve as model parameter beyond lipophilicity.

Speciation of selenium in environmental samples by solid-phase spectrophotometry using 2,3-dichloro-6-(2,7-dihydroxy-naphthylazo)quinoxaline.

PubMed

Amin, Alaa S

2014-01-01

Solid-phase spectrophotometry was applied to determination of trace amounts of selenium (Se) in water, soil, plant materials, human hair, and a cosmetic preparation (lipstick). Se(IV) was sorbed in a dextran type lipophilic gel as a complex with 2,3-dichloro-6-(2,7-dihydroxy-naphthylazo)quinoxaline (DCDHNAQ), whereas Se(VI) was determined after boiling in HCI for 10 min to convert Se(VI) to Se(IV). Resin phase absorbances at 588 and 800 nm were measured directly, which allowed the determination of Se in the range of 0.2-3.3 microg/L with an RSD of 1.22%. The influences of analytical parameters including pH of the aqueous solution, amounts of DCDHNAQ, and sample volume were investigated. The molar absorptivities were found to be 1.09 x 10(6), 4.60 x 10(6), and 1.23 x 10(7) L/mol cm for 100, 500, and 1000 mL, respectively. The LOD and LOQ of the 500 mL sample method were 110 and 360 ng/L, respectively, when using 50 mg dextran type lipophilic gel. For a 1000 mL sample, the LOD and LOQ were 60 and 200 ng/L, respectively, using 50 mg of the exchanger. Increasing the sample volume enhanced the sensitivity. No considerable interferences were observed from other investigated anions and cations on the Se determination.

Enhanced Antibacterial Activity of Ent-Labdane Derivatives of Salvic Acid (7α-Hydroxy-8(17)-ent-Labden-15-Oic Acid): Effect of Lipophilicity and the Hydrogen Bonding Role in Bacterial Membrane Interaction.

PubMed

Echeverría, Javier; Urzúa, Alejandro; Sanhueza, Loreto; Wilkens, Marcela

2017-06-23

In the present study, the antibacterial activity of several ent -labdane derivatives of salvic acid (7α-hydroxy-8(17)- ent -labden-15-oic acid) was evaluated in vitro against the Gram-negative bacterium Escherichia coli and the Gram-positive bacteria Staphylococcus aureus and Bacillus cereus . For all of the compounds, the antibacterial activity was expressed as the minimum inhibitory concentration (MIC) in liquid media and minimum inhibitory amount (MIA) in solid media. Structure activity relationships (SAR) were employed to correlate the effect of the calculated lipophilicity parameters (logP ow ) on the inhibitory activity. Employing a phospholipidic bilayer (POPG) as a bacterial membrane model, ent -labdane-membrane interactions were simulated utilizing docking studies. The results indicate that (i) the presence of a carboxylic acid in the C-15 position, which acted as a hydrogen-bond donor (HBD), was essential for the antibacterial activity of the ent -labdanes; (ii) an increase in the length of the acylated chain at the C-7 position improved the antibacterial activity until an optimum length of five carbon atoms was reached; (iii) an increase in the length of the acylated chain by more than five carbon atoms resulted in a dramatic decrease in activity, which completely disappeared in acyl chains of more than nine carbon atoms; and (iv) the structural factors described above, including one HBD at C-15 and a hexanoyloxi moiety at C-7, had a good fit to a specific lipophilic range and antibacterial activity. The lipophilicity parameter has a predictive characteristic feature on the antibacterial activity of this class of compounds, to be considered in the design of new biologically active molecules.

Poly(aniline) nanowires in sol-gel coated ITO: A pH-responsive substrate for planar supported lipid bilayers

PubMed Central

Ge, Chenhao; Orosz, Kristina S.; Armstrong, Neal R.; Saavedra, S. Scott

2011-01-01

Facilitated ion transport across an artificial lipid bilayer coupled to a solid substrate is a function common to several types of bioelectronic devices based on supported membranes, including biomimetic fuel cells and ion channel biosensors. Described here is fabrication of a pH-sensitive transducer composed of a porous sol-gel layer derivatized with poly(aniline) (PANI) nanowires grown from an underlying planar indium-tin oxide (ITO) electrode. The upper sol-gel surface is hydrophilic, smooth, and compatible with deposition of a planar supported lipid bilayer (PSLB) formed via vesicle fusion. Conducting tip AFM was used to show that the PANI wires are connected to the ITO, which convert this electrode into a potentiometric pH sensor. The response to changes in the pH of the buffer contacting the PANI nanowire/sol-gel/ITO electrode is blocked by the very low ion permeability of the overlying, fluid PSLB. The feasibility of using this assembly to monitor facilitated proton transport across the PSLB was demonstrated by doping the membrane with lipophilic ionophores that respond to a transmembrane pH gradient, which produced an apparent proton permeability several orders of magnitude greater than values measured for undoped lipid bilayers. PMID:21707069

Retention and release of oil-in-water emulsions from filled hydrogel beads composed of calcium alginate: impact of emulsifier type and pH.

PubMed

Zeeb, Benjamin; Saberi, Amir Hossein; Weiss, Jochen; McClements, David Julian

2015-03-21

Delivery systems based on filled hydrogel particles (microgels) can be fabricated from natural food-grade lipids and biopolymers. The potential for controlling release characteristics by modulating the electrostatic interactions between emulsifier-coated lipid droplets and the biopolymer matrix within hydrogel particles was investigated. A multistage procedure was used to fabricate calcium alginate beads filled with lipid droplets stabilized by non-ionic, cationic, anionic, or zwitterionic emulsifiers. Oil-in-water emulsions stabilized by Tween 60, DTAB, SDS, or whey protein were prepared by microfluidization, mixed with various alginate solutions, and then microgels were formed by simple extrusion into calcium solutions. The microgels were placed into a series of buffer solutions with different pH values (2 to 11). Lipid droplets remained encapsulated under acidic and neutral conditions, but were released under highly basic conditions (pH 11) due to hydrogel swelling when the alginate concentration was sufficiently high. Lipid droplet release increased with decreasing alginate concentration, which could be attributed to an increase in the pore size of the hydrogel matrix. These results have important implications for the design of delivery systems to entrap and control the release of lipophilic bioactive components within filled hydrogel particles.

Equilibrium partitioning of organic compounds to OASIS HLB® as a function of compound concentration, pH, temperature and salinity.

PubMed

Jeong, Yoonah; Schäffer, Andreas; Smith, Kilian

2017-05-01

Oasis hydrophilic lipophilic balance ® (Oasis HLB) is commonly employed in solid phase extraction (SPE) of environmental contaminants and within polar organic chemical integrative passive samplers (POCIS). In this study batch experiments were carried out to evaluate the relative affinity of a range of relevant organic pollutants to Oasis HLB in aqueous systems. The influence of sorbate concentration, temperature, pH, and salinity on the equilibrium sorption was investigated. Equilibrium partition ratios (K D ) of 28 compounds were determined, ranging over three orders of magnitude from 1.16 × 10 3  L/kg (atenolol) to 1.07 × 10 6  L/kg (isoproturon). The Freundlich model was able to describe the equilibrium partitioning to Oasis HLB, and an analysis of the thermodynamic parameters revealed the spontaneous and exothermic nature of the partitioning process. Ionic strength had only a minor effect on the partitioning, whereas pH had a considerable effect but only for ionizable compounds. The results show that apolar interactions between the Oasis HLB and analyte mainly determine the equilibrium partitioning. These research findings can be used to optimize the application of SPE and POCIS for analyses of environmental contaminants even in complex mixtures. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Choosing the correct benzodiazepine: mechanism of action and pharmacokinetics].

PubMed

Vinkers, Christiaan H; Tijdink, Joeri K; Luykx, Jurjen J; Vis, Roeland

2012-01-01

There is a discrepancy between the recommendation for caution and daily practice in the prescription of benzodiazepines. Although there is heterogeneity in the registered indications, all benzodiazepine agonists have almost the same mechanism of action. There are, however, substantial pharmacokinetic differences between individual benzodiazepine agonists. During short-term use of benzodiazepines, the elimination half-life is no measure of duration of action. Benzodiazepine lipophilicity determines the speed of action. If a rapid effect is desired, for instance in acute anxiety or agitation, then regarding oral medication the use of a lipophilic benzodiazepine such as diazepam is a rational choice. An accumulation factor can be used to estimate benzodiazepine accumulation during chronic use. In theory, accumulation does not occur with once-daily dosage of benzodiazepines that have an elimination half-life markedly shorter than 24 h, such as oxazepam, temazepam, and lorazepam.

The antimalarial activity of Ru–chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces

PubMed Central

Martínez, Alberto; Rajapakse, Chandima S. K.; Jalloh, Dalanda; Dautriche, Cula

2012-01-01

We have measured water/n-octanol partition coefficients, pKa values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium–πarene–chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied. PMID:19343380

The antimalarial activity of Ru-chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces.

PubMed

Martínez, Alberto; Rajapakse, Chandima S K; Jalloh, Dalanda; Dautriche, Cula; Sánchez-Delgado, Roberto A

2009-08-01

We have measured water/n-octanol partition coefficients, pK(a) values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium-pi-arene-chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied.

Solubility, ionization, and partitioning behavior of unsymmetrical disulfide compounds: alkyl 2-imidazolyl disulfides.

PubMed

Hashash, Ahmad; Kirkpatrick, D Lynn; Lazo, John S; Block, Lawrence H

2002-07-01

Alkyl 2-imidazolyl disulfide compounds are novel antitumor agents, one of which is currently being evaluated in Phase I clinical trials. These molecules contain an unsymmetrical disulfide fragment, the lipophilic and electronic contributions of which are still not defined in the literature. Lipophilicity, ionization, and solubility of a number of alkyl 2-imidazolyl disulfides were studied. Based on the additivity of lipophilicity and ionization properties, the contribution of the unsymmetrical disulfide fragment to lipophilicity and ionization was elucidated. The unsymmetrical disulfide fragment contributed a Rekker's hydrophobic constant of 0.761 to the lipophilicity of these compounds and an approximated Hammett constant (sigma) of 0.30 to their ionization. The applicability of the general solubility equation (GSE) proposed by Jain and Yalkowsky in predicting the aqueous solubility of these analogs was evaluated. The GSE correctly ranked the aqueous solubilities of these compounds and estimated their log molar solubilities with an average absolute error of 0.35. Copyright 2002 Wiley-Liss Inc.

Effect of solute lipophilicity on penetration through canine skin.

PubMed

Mills, P C; Magnusson, B M; Cross, S E

2003-12-01

To investigate the effect of lipophilicity on the percutaneous penetration of a homologous series of alcohols through canine skin. Skin harvested from Greyhound thorax was placed in Franz-type diffusion cells and the in vitro passage of radiolabelled (14C) alcohols (ethanol, butanol, hexanol and octanol (Log P 0.19-3.0)) through separate skin sections was measured in replicates of five. Permeability coefficient (kP, cm/h), maximum flux (Jmax, mol/cm2/h) and residue remaining within the skin were determined. The kP increased with increasing lipophilicity (6.2 x 10(-4) +/- 1.6 x 10(-4) cm/h for ethanol to 1.8 x 10(-2) +/- 3.6 x 10(-3) cm/h for octanol). Alcohol residues remaining within each skin sample followed a similar pattern. An exponential decrease in Jmax with increasing lipophilicity was observed. Changes in canine skin permeability occur with increasing alcohol lipophilicity. This finding has practical consequences for the design of topical formulations and optimisation of drug delivery through animal skin.

The potential signalling pathways which regulate surface changes induced by phytohormones in the potato cyst nematode (Globodera rostochiensis).

PubMed

Akhkha, A; Curtis, R; Kennedy, M; Kusel, J

2004-05-01

It has been demonstrated that the surface lipophilicity of the plant-parasitic nematode Globodera rostochiensis decreases when infective larvae are exposed to the phytohormones indole-3-acetic acid (auxin) or kinetin (cytokinin). In the present study, it was shown that inhibition of phospholipase C (PLC) or phosphatidylinositol 3 kinase (PI3-kinase) reversed the effect of phytohormones on surface lipophilicity. The signalling pathway(s) involved in surface modification were investigated using 'caged' signalling molecules and stimulators or inhibitors of different signalling enzymes. Photolysis of the 'caged' signalling molecules, NPE-caged Ins 1,4,5-P3, NITR-5/AM or caged-cAMP to liberate IP3, Ca2+ or cAMP respectively, decreased the surface lipophilicity. Activation of adenylate cyclase also decreased the surface lipophilicity. In contrast, inhibition of PI3-kinase using Wortmannin, LY-294002 or Quercetin, and inhibition of PLC using U-73122 all increased the surface lipophilicity. Two possible signalling pathways involved in phytohormone-induced surface modification are proposed.

Occupational Asthma Due to Inhalation of Aerosolized Lipophilic Coating Materials.

PubMed

Suresh, Karthik; Belchis, Deborah; Askin, Fred; Pearse, David B; Terry, Peter B

2016-10-01

We present a case of onset of severe asthma in a 59-year-old patient who worked in an aerospace plant. He was noted to have wheezing on exam and obstruction on PFTs. Review of his occupational history revealed exposure to lipophilic industrial compounds. We outline the radiographic and histologic findings that were found in the patient, and discuss occupational asthma due to inhalation of lipophilic compounds.

Assays for hydrophilic and lipophilic antioxidant capacity (oxygen radical absorbance capacity (ORAC(FL))) of plasma and other biological and food samples.

PubMed

Prior, Ronald L; Hoang, Ha; Gu, Liwei; Wu, Xianli; Bacchiocca, Mara; Howard, Luke; Hampsch-Woodill, Maureen; Huang, Dejian; Ou, Boxin; Jacob, Robert

2003-05-21

Methods are described for the extraction and analysis of hydrophilic and lipophilic antioxidants, using modifications of the oxygen radical absorbing capacity (ORAC(FL)) procedure. These methods provide, for the first time, the ability to obtain a measure of "total antioxidant capacity" in the protein free plasma, using the same peroxyl radical generator for both lipophilic and hydrophilic antioxidants. Separation of the lipophilic and hydrophilic antioxidant fractions from plasma was accomplished by extracting with hexane after adding water and ethanol to the plasma (hexane/plasma/ethanol/water, 4:1:2:1, v/v). Lipophilic and hydrophilic antioxidants were efficiently partitioned between hexane and aqueous solvents. Conditions for controlling temperature effects and decreasing assay variability using fluorescein as the fluorescent probe were validated in different laboratories. Incubation (37 degrees C for at least 30 min) of the buffer to which AAPH was dissolved was critical in decreasing assay variability. Lipophilic antioxidants represented 33.1 +/- 1.5 and 38.2 +/- 1.9% of the total antioxidant capacity of the protein free plasma in two independent studies of 6 and 10 subjects, respectively. Methods are described for application of the assay techniques to other types of biological and food samples.

Effect of menthone and related compounds on skin permeation of drugs with different lipophilicity and molecular organization of stratum corneum lipids.

PubMed

Lan, Yi; Wang, Jingyan; Li, Hui; Zhang, Yewen; Chen, Yanyan; Zhao, Bochen; Wu, Qing

2016-01-01

The objective of this article was to investigate the enhancing effect of menthone, menthol and pulegone on the transdermal absorption of drugs with different lipophilicity and probe their mechanisms of action at molecular level. Five model drugs, namely osthole, tetramethylpyrazine, ferulic acid, puerarin and geniposide, which were selected based on their lipophilicity denoted by logKo/w, were tested using in vitro permeation studies in which Franz diffusion cells and rat skin were employed. Infrared spectroscopy and molecular dynamic simulation were used to investigate the effect of these enhancers on the stratum corneum (SC) lipids, respectively. Three compounds could effectively promote the transdermal absorption of drugs with different lipophilicity, and the overall promoting capacities were in the following increasing order: pulegone < menthol < menthone. The penetration enhancement ratio was roughly in parabolic curve relationships with the drug lipophilicity after treatment with menthol or menthone, while the penetration enhancement effect of pulegone hardly changed with the alteration of the drug lipophilicity. The molecular mechanism studies suggested that menthone and menthol enhanced the skin permeability by disordering the ordered organization of SC lipids and extracted part of SC lipids, while pulegone appeared to promote drug transport across the skin only by extracting part of SC lipids.

Alternative measures of lipophilicity: from octanol-water partitioning to IAM retention.

PubMed

Giaginis, Costas; Tsantili-Kakoulidou, Anna

2008-08-01

This review describes lipophilicity parameters currently used in drug design and QSAR studies. After a short historical overview, the complex nature of lipophilicity as the outcome of polar/nonpolar inter- and intramolecular interactions is analysed and considered as the background for the discussion of the different lipophilicity descriptors. The first part focuses on octanol-water partitioning of neutral and ionisable compounds, evaluates the efficiency of predictions and provides a short description of the experimental methods for the determination of distribution coefficients. A next part is dedicated to reversed-phase chromatographic techniques, HPLC and TLC in lipophilicity assessment. The two methods are evaluated for their efficiency to simulate octanol-water and the progress achieved in the refinement of suitable chromatographic conditions, in particular in the field of HPLC, is outlined. Liposomes as direct models of biological membranes are examined and phospolipophilicity is compared to the traditional lipophilicity concept. Difficulties associated with liposome-water partitioning are discussed. The last part focuses on Immobilised Artificial Membrane (IAM) chromatography as an alternative which combines membrane simulation with rapid measurements. IAM chromatographic retention is compared to octanol-water and liposome-water partitioning as well as to reversed-phase retention and its potential to predict biopartitioning and biological activities is discussed.

The potential of immobilized artificial membrane chromatography to predict human oral absorption.

PubMed

Tsopelas, Fotios; Vallianatou, Theodosia; Tsantili-Kakoulidou, Anna

2016-01-01

The potential of immobilized artificial membrane (IAM) chromatography to estimate human oral absorption (%HOA) was investigated. For this purpose, retention indices on IAM stationary phases reported previously by our group or measured by other authors under similar conditions were used to model %HOA data, compiled from literature sources. Considering the pH gradient in gastrointestinal tract, the highest logkw(IAM) values were considered, obtained either at pH7.4 or 5.5, defined as logkw(IAM)(best). Non linear models were established upon introduction of additional parameters and after exclusion of drugs which are substrates either to efflux or uptake transporters. The best model included Abraham's hydrogen-bond acidity parameter, molecular weight as well as the positively and negatively charged molecular fractions. For reasons of comparison between IAM chromatography and traditional lipophilicity, corresponding models were derived by replacing IAM retention factors with octanol-water distribution coefficients (logD). An overexpression of electrostatic interactions with phosphate anions was observed in the case of IAM retention as expressed by the negative contribution of the positively charged fraction F(+). The same parameter is statistically significant also in the logD model, but with a positive sign, indicating the attraction of basic drugs in the negatively charged inner membrane. To validate the obtained models a blind test set of 22 structurally diverse drugs was used, whose logkw(IAM)(best) values were determined and analyzed in the present study under similar conditions. IAM retention factors were further compared with MDCK cell lines permeability data taken from literature for a set of validation drugs. The overexpression of electrostatic interactions with phosphate anions on IAM surface was also evident in respect to MDCK permeability. In contrast to the clear classification between drugs with high and poor (or intermediate) absorption provided by MDCK permeability, %HOA plotted versus both IAM and logD data result in a saturation curve with a smoother ascending line. Copyright © 2015 Elsevier B.V. All rights reserved.

Structure-Activity and Lipophilicity Relationships of Selected Antibacterial Natural Flavones and Flavanones of Chilean Flora.

PubMed

Echeverría, Javier; Opazo, Julia; Mendoza, Leonora; Urzúa, Alejandro; Wilkens, Marcela

2017-04-10

In this study, we tested eight naturally-occurring flavonoids-three flavanones and five flavones-for their possible antibacterial properties against four Gram-positive and four Gram-negative bacteria. Flavonoids are known for their antimicrobial properties, and due their structural diversity; these plant-derived compounds are a good model to study potential novel antibacterial mechanisms. The lipophilicity and the interaction of antibacterial compounds with the cell membrane define the success or failure to access its target. Therefore, through the determination of partition coefficients in a non-polar/aqueous phase, lipophilicity estimation and the quantification of the antibacterial activity of different flavonoids, flavanones, and flavones, a relationship between these parameters was assessed. Active flavonoids presented diffusion coefficients between 9.4 × 10 -10 and 12.3 × 10 -10 m²/s and lipophilicity range between 2.0 to 3.3. Active flavonoids against Gram-negative bacteria showed a narrower range of lipophilicity values, compared to active flavonoids against Gram-positive bacteria, which showed a wide range of lipophilicity and cell lysis. Galangin was the most active flavonoid, whose structural features are the presence of two hydroxyl groups located strategically on ring A and the absence of polar groups on ring B. Methylation of one hydroxyl group decreases the activity in 3- O -methylgalangin, and methylation of both hydroxyl groups caused inactivation, as shown for 3,7- O -dimethylgalangin. In conclusion, the amphipathic features of flavonoids play a crucial role in the antibacterial activity. In these compounds, hydrophilic and hydrophobic moieties must be present and could be predicted by lipophilicity analysis.

[Partitioning of taxifolin-iron ions complexes in octanol-water system].

PubMed

Shatalin, Iu V; Shubina, V S

2014-01-01

The composition of taxifolin-iron ions complexes in an octanol-water biphasic system was studied using the method of absorption spectrophotometry. It was found that at pH 5.0 in an aqueous biphasic system the complex of [Tf2 x Fe x (OH)k(H2O)8-k] is present, but at pH 7.0 and 9.0 the complexes of [Tf2 x Fe x (OH)k(H2O)2-k] and [Tf x Fe x OH)k(H2O)4-k] are predominantly observed. The formation of a stable [Tf3 x Fe] complex occurred in octanol phase. The charged iron ion of this complex is surrounded by taxifolin molecules, which shield the iron ion from lipophilic solvent. During transition from water to octanol phase the changes of the composition of complexes are accompanied by reciprocal changes in portion of taxifolin and iron ions in these phases. It was shown that the portion of taxifolin in aqueous solution in the presence of iron ions is increased at high pH values, and the portion of iron ions is minimal at pH 7.0. In addition, the parameters of solubility limits of taxifolin-iron ions complexes in an aqueous solution were determined. The data obtained gain a better understanding of the role of complexation of polyphenol with metal of variable valency in passive transport of flavonoids and metal ions across lipid membranes.

Reduction in lipophilicity improved the solubility, plasma–protein binding, and permeability of tertiary sulfonamide RORc inverse agonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fauber, Benjamin P.; René, Olivier; de Leon Boenig, Gladys

2014-08-01

Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma–protein unbound fraction and improvements in cellular permeability and aqueous solubility.

Hydrophobicity and biofilm formation of lipophilic skin corynebacteria.

PubMed

Kwaszewska, Anna K; Brewczyńska, Anna; Szewczyk, Eligia M

2006-01-01

Lipophilic corynebacteria isolated as natural flora of human skin were examined. Among 119 assayed strains 94% presented a hydrophobic cell surface and 75.6% were able to form biofilms. These attributes, as well as aggregation in liquid media, were statistically connected with each other and promote the developing of biofilms on solid surfaces. This was characteristic of all the lipophilic Corynebacterium species found on human skin that were examined in this study. C. jeikeium and CDC group G2 strains dominated in this population, and they could be responsible for investigated features in the whole lipophilic skin bacterial population. These two groups are the most common coryneform bacteria isolated from nosocomial infections and these attributes most likely promote them to cause opportunistic infections.

Miscanthus x giganteus bark organosolv fractionation: fate of lipophilic components and formation of valuable phenolic byproducts.

PubMed

Villaverde, Juan José; De Vega, Alberto; Ligero, Pablo; Freire, Carmen S R; Neto, Carlos Pascoal; Silvestre, Armando J D

2010-07-28

The behavior of Miscanthus x giganteus bark lipophilic extractives during three acid organosolv pulping processes (Acetosolv, formic acid fractionation, and Milox) was investigated. It was demonstrated that nearly 90% of the lipophilic extractives were removed from pulps by either dissolution in the organosolv liquors (fatty acids and alcohols) or extensive degradation (sterols). The organosolv liquors were found to be rich in vanillin, syringaldehyde, and ferulic, vanillic, and p-coumaric acids. The Acetosolv fractionation process was found to be the most efficient in the removal of lipophilic components from pulps, and it was also the process that generated higher amounts of valuable monomeric phenolic compounds that could be exploited within the biorefinery context.

Semisolid matrix filled capsules: an approach to improve dissolution stability of phenytoin sodium formulation.

PubMed

El Massik, M A; Abdallah, O Y; Galal, S; Daabis, N A

2003-05-01

Seven semisolid fill bases were selected for the formulation of 24 capsule formulations, each containing 100 mg of phenytoin sodium. The fill materials were selected based on the water absorption capacity of their mixtures with phenytoin sodium. The fill matrices included lipophilic bases (castor oil, soya oil, and Gelucire (G) 33/01), amphiphilic bases (G 44/14 and Suppocire BP), and water-soluble bases (PEG 4000 and PEG 6000). The drug:base ratio was 1:2. Excipients such as lecithin, docusate sodium, and poloxamer 188 were added to some formulations. The dissolution rate study indicated that formulations containing lipophilic and amphiphilic bases showed the best release profiles. These are F4 (castor oil-1% docusate sodium); F10 (castor oil-3% poloxamer 188); F14 (G33/01-10% lecithin); F17 (G33/01-1% docusate sodium), and F20 (Suppocire BP). Further, the dissolution stability of the five formulations above was assessed by an accelerated stability study at 30 degrees C and 75% RH using standard Epanutin capsules for comparison. The study included the test and standard capsules either packed in the container of marketed Epanutin capsules (packed) or removed from their outer pack (unpacked). Release data indicated superior release rates of castor oil based formulations (F4 and F10) relative to standard capsules in both the unpacked and packed forms. For instance, the extent of drug release at 30 min after 1 month was 91% for F4 and F10 and 20% for standard capsules. Drug release from packed capsules after 6 months storage was 88% for both formulations F4 and F10 and 35% for standard capsules. In conclusion, the pharmaceutical quality of phenytoin sodium capsules can be improved by using a semisolid lipophilic matrix filled in hard gelatin capsules.

A validated UPLC-MS/MS method for the analysis of linezolid and a novel oxazolidinone derivative (PH027) in plasma and its application to tissue distribution study in rabbits.

PubMed

Hedaya, Mohsen A; Thomas, Vidhya; Abdel-Hamid, Mohamed E; Kehinde, Elijah O; Phillips, Oludotun A

2017-01-01

Linezolid is the first approved oxazolidinone antibacterial agent, whereas PH027 is a novel compound of the same class that exhibits good in vitro antibacterial activity. The objective of this study was to develop an UPLC-MS/MS assay for the analysis of linezolid and PH027 in plasma and to apply the method for comparative pharmacokinetic and tissue distribution studies of both compounds. Plasma samples and calibrators were extracted with diethyl ether after addition of the internal standard solution. After evaporation of the ether layer, the residue was reconstituted in mobile phase and injected into UPLC-MS/MS. The mobile phase consisted of 2mM ammonium acetate buffer solution and acetonitrile (70:30) at a flow rate of 0.2ml/min. Separation was achieved using UPLC BEH C 18 column, and quantitative determination of the analytes was performed using multiple-reaction monitoring (MRM) scanning mode. The method was validated by analyzing quality control tissue homogenate samples, and was applied to analyze tissue homogenate samples obtained following IV injections of linezolid and PH027 in rabbits. The developed UPLC-MS/MS method was linear in the concentration range of 50-5000ng/ml. Validation of the method proved that the method's precision, selectivity and stability were all within the acceptable limits. Linezolid and PH027 concentrations were accurately determined in the quality control tissue homogenate samples, and analysis of samples obtained following IV administration of the two compounds showed that the tissue to plasma concentration ratio of PH027 was higher than that of linezolid probably due to its higher lipophilicity. The developed UPLC-MS/MS method for the analysis of linezolid and PH027 in rabbit's plasma can accurately determine the concentrations of these compounds in different tissues. Copyright © 2016 Elsevier B.V. All rights reserved.

Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group.

PubMed

Petrova, Natalya S; Chernikov, Ivan V; Meschaninova, Mariya I; Dovydenko, Iiya S; Venyaminova, Aliya G; Zenkova, Marina A; Vlassov, Valentin V; Chernolovskaya, Elena L

2012-03-01

The conjugation of siRNA to molecules, which can be internalized into the cell via natural transport mechanisms, can result in the enhancement of siRNA cellular uptake. Herein, the carrier-free cellular uptake of nuclease-resistant anti-MDR1 siRNA equipped with lipophilic residues (cholesterol, lithocholic acid, oleyl alcohol and litocholic acid oleylamide) attached to the 5'-end of the sense strand via oligomethylene linker of various length was investigated. A convenient combination of H-phosphonate and phosphoramidite methods was developed for the synthesis of 5'-lipophilic conjugates of siRNAs. It was found that lipophilic siRNA are able to effectively penetrate into HEK293, HepG2 and KB-8-5 cancer cells when used in a micromolar concentration range. The efficiency of the uptake is dependent upon the type of lipophilic moiety, the length of the linker between the moiety and the siRNA and cell type. Among all the conjugates tested, the cholesterol-conjugated siRNAs with linkers containing from 6 to 10 carbon atoms demonstrate the optimal uptake and gene silencing properties: the shortening of the linker reduces the efficiency of the cellular uptake of siRNA conjugates, whereas the lengthening of the linker facilitates the uptake but retards the gene silencing effect and decreases the efficiency of the silencing.

Prescription of lipophilic statins to Alzheimer's disease patients: some controversies to consider.

PubMed

Biondi, Elisa

2011-04-01

Alzheimer's disease (AD) is the most common disorder causing cognitive decline in old age. It is a progressive and irreversible neuropathology with a diagnosis often missed or delayed. Cholesterol represents an important determinant of the physical state of biological membranes and in AD brains, specific changes in its membrane-ordering and Raft-organizing effects take place. A recent publication shows downregulation of Seladin-1 (selective Alzheimer's disease indicator, also called DHCR24), which catalyzes the last step of cholesterol biosynthesis in affected neurons in AD. Postmortem analysis of AD brains revealed a loss in membrane cholesterol content and this finding makes the therapeutical use of statins (especially the lipophilic ones) quite a lot controversial. Some clinical studies suggest that risk of Alzheimer's disease is substantially reduced in users of statins; however, because these studies are not randomized trials, they provide insufficient evidence to recommend statin family therapy.

Sea buckthorn (Hippophae rhamnoides L.) vegetative parts as an unconventional source of lipophilic antioxidants.

PubMed

Górnaś, Paweł; Šnē, Elga; Siger, Aleksander; Segliņa, Dalija

2016-07-01

The profile of lipophilic antioxidants in different vegetative parts (leaves, shoots, buds and berries) was studied in sea buckthorn (Hippophae rhamnoides L.) male and female plants collected in the end of spring. Five lipophilic compounds, i.e. three tocopherol homologues (α, β and γ), plastochromanol-8 and β-carotene, were identified in each vegetative part of male and female sea buckthorn plants at the following concentrations: 7.25-35.41, 0.21-2.43, 0.41-1.51, 0.19-1.79 and 4.43-24.57 mg/100 g dry weight basis. Additionally, significant amounts of α-tocotrienol (1.99 mg/100 g dry weight basis) were detected in buds. The α-tocopherol and β-carotene were predominant lipophilic antioxidants in each vegetative part, accounting for 78.3-97.0% of identified compounds. The greatest amounts of lipophilic antioxidants were found in leaves, especially of female plants. Nevertheless, apart from leaves, also shoots of plants of both sexes seem to be a good source of α-tocopherol and β-carotene.

Correlation of antimutagenic activity and suppression of CYP1A with the lipophilicity of alkyl gallates and other phenolic compounds.

PubMed

Feng, Qing; Kumagai, Takeshi; Nakamura, Yoshimasa; Uchida, Koji; Osawa, Toshihiko

2003-05-09

Alkyl gallates are widely used as food antioxidants. Methyl, ethyl, propyl, lauryl, and cetyl gallates showed antimutagenicity to activated 2-aminoanthracene (2AA)-induced SOS responses in Salmonella typhimurium TA1535/pSK1002. They also exhibited a suppressive effect on 3-methylcholanthrene (3-MC)-induced cytochrome P450 1A (CYP1A) in human hepatoma HepG2 cells, as indexed by the 7-ethoxyresorufin-O-deethylase (EROD) activity, and on CYP1A protein level. Both antimutagenicity and suppression of CYP1A appeared to be dependent on alkyl chain lengths, which suggested lipophilicity dependence. Based on those results, we investigated 26 other phenolic compounds for their lipophilicity, antimutagenicity and inhibition of EROD activity. The lipophilicity correlated well with the inhibition of EROD activity (r=0.78), and the inhibition of EROD activity correlated with the antimutagenicity of those compounds (r=0.71). The results suggest that the lipophilicity of the phenolic compounds may be an important factor in their ability to inhibit EROD activity.

PBDE CONTAMINATION OF U.S. FOOD AND HUMAN MILK, AND PBDE, PCDD/F, PCB, AND LEVELS IN U. S. HUMAN BLOOD (1973 AND 2003)

EPA Science Inventory

Introduction
Historical exposure trends to persistent organic pollutants (POPs) indicate that the primary route of exposure in humans is traditionally dietary intake, contributing to a steady-state body burden of these lipophilic chemicals, which are also transported to offspr...

Around the macrolide - Impact of 3D structure of macrocycles on lipophilicity and cellular accumulation.

PubMed

Koštrun, Sanja; Munic Kos, Vesna; Matanović Škugor, Maja; Palej Jakopović, Ivana; Malnar, Ivica; Dragojević, Snježana; Ralić, Jovica; Alihodžić, Sulejman

2017-06-16

The aim of this study was to investigate lipophilicity and cellular accumulation of rationally designed azithromycin and clarithromycin derivatives at the molecular level. The effect of substitution site and substituent properties on a global physico-chemical profile and cellular accumulation of investigated compounds was studied using calculated structural parameters as well as experimentally determined lipophilicity. In silico models based on the 3D structure of molecules were generated to investigate conformational effect on studied properties and to enable prediction of lipophilicity and cellular accumulation for this class of molecules based on non-empirical parameters. The applicability of developed models was explored on a validation and test sets and compared with previously developed empirical models. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Endocytotic uptake of HPMA-based polymers by different cancer cells: impact of extracellular acidosis and hypoxia

PubMed Central

Gündel, Daniel; Allmeroth, Mareli; Reime, Sarah; Zentel, Rudolf; Thews, Oliver

2017-01-01

Background Polymeric nanoparticles allow to selectively transport chemotherapeutic drugs to the tumor tissue. These nanocarriers have to be taken up into the cells to release the drug. In addition, tumors often show pathological metabolic characteristics (hypoxia and acidosis) which might affect the polymer endocytosis. Materials and methods Six different N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer structures (homopolymer as well as random and block copolymers with lauryl methacrylate containing hydrophobic side chains) varying in molecular weight and size were analyzed in two different tumor models. The cellular uptake of fluorescence-labeled polymers was measured under hypoxic (pO2 ≈1.5 mmHg) and acidic (pH 6.6) conditions. By using specific inhibitors, different endocytotic routes (macropinocytosis and clathrin-mediated, dynamin-dependent, cholesterol-dependent endocytosis) were analyzed separately. Results The current results revealed that the polymer uptake depends on the molecular structure, molecular weight and tumor line used. In AT1 cells, the uptake of random copolymer was five times stronger than the homopolymer, whereas in Walker-256 cells, the uptake of all polymers was much stronger, but this was independent of the molecular structure and size. Acidosis increased the uptake of random copolymer in AT1 cells but reduced the intracellular accumulation of homopolymer and block copolymer. Hypoxia reduced the uptake of all polymers in Walker-256 cells. Hydrophilic polymers (homopolymer and block copolymer) were taken up by all endocytotic routes studied, whereas the more lipophilic random copolymer seemed to be taken up preferentially by cholesterol- and dynamin-dependent endocytosis. Conclusion The study indicates that numerous parameters of the polymer (structure, size) and of the tumor (perfusion, vascular permeability, pH, pO2) modulate drug delivery, which makes it difficult to select the appropriate polymer for the individual patient. PMID:28831253

Endocytotic uptake of HPMA-based polymers by different cancer cells: impact of extracellular acidosis and hypoxia.

PubMed

Gündel, Daniel; Allmeroth, Mareli; Reime, Sarah; Zentel, Rudolf; Thews, Oliver

2017-01-01

Polymeric nanoparticles allow to selectively transport chemotherapeutic drugs to the tumor tissue. These nanocarriers have to be taken up into the cells to release the drug. In addition, tumors often show pathological metabolic characteristics (hypoxia and acidosis) which might affect the polymer endocytosis. Six different N -(2-hydroxypropyl)methacrylamide (HPMA)-based polymer structures (homopolymer as well as random and block copolymers with lauryl methacrylate containing hydrophobic side chains) varying in molecular weight and size were analyzed in two different tumor models. The cellular uptake of fluorescence-labeled polymers was measured under hypoxic (pO 2 ≈1.5 mmHg) and acidic (pH 6.6) conditions. By using specific inhibitors, different endocytotic routes (macropinocytosis and clathrin-mediated, dynamin-dependent, cholesterol-dependent endocytosis) were analyzed separately. The current results revealed that the polymer uptake depends on the molecular structure, molecular weight and tumor line used. In AT1 cells, the uptake of random copolymer was five times stronger than the homopolymer, whereas in Walker-256 cells, the uptake of all polymers was much stronger, but this was independent of the molecular structure and size. Acidosis increased the uptake of random copolymer in AT1 cells but reduced the intracellular accumulation of homopolymer and block copolymer. Hypoxia reduced the uptake of all polymers in Walker-256 cells. Hydrophilic polymers (homopolymer and block copolymer) were taken up by all endocytotic routes studied, whereas the more lipophilic random copolymer seemed to be taken up preferentially by cholesterol- and dynamin-dependent endocytosis. The study indicates that numerous parameters of the polymer (structure, size) and of the tumor (perfusion, vascular permeability, pH, pO 2 ) modulate drug delivery, which makes it difficult to select the appropriate polymer for the individual patient.

Novel Cu(I)-selective chelators based on a bis(phosphorothioyl)amide scaffold.

PubMed

Amir, Aviran; Ezra, Alon; Shimon, Linda J W; Fischer, Bilha

2014-08-04

Bis(dialkyl/aryl-phosphorothioyl)amide (BPA) derivatives are versatile ligands known by their high metal-ion affinity and selectivity. Here, we synthesized related chelators based on bis(1,3,2-dithia/dioxaphospholane-2-sulfide)amide (BTPA/BOPA) scaffolds targeting the chelation of soft metal ions. Crystal structures of BTPA compounds 6 (N(-)R3NH(+)) and 8 (NEt) revealed a gauche geometry, while BOPA compound 7 (N(-)R3NH(+)) exhibited an anti-geometry. Solid-state (31)P magic-angle spinning NMR spectra of BTPA 6-Hg(II) and 6-Zn(II) complexes imply a square planar or tetrahedral geometry of the former and a distorted tetrahedral geometry of the latter, while both BTPA 6-Ni(II) and BOPA 7-Ni(II) complexes possibly form a polymeric structure. In Cu(I)-H2O2 system (Fenton reaction conditions) BTPA compounds 6, 8, and 10 (NCH2Ph) were identified as most potent antioxidants (IC50 32, 56, and 29 μM, respectively), whereas BOPA analogues 7, 9 (NEt), and 11 (NCH2Ph) were found to be poor antioxidants. In Fe(II)-H2O2 system, IC50 values for both BTPA and BOPA compounds exceeded 500 μM indicating high selectivity to Cu(I) versus the borderline Fe(II)-ion. Neither BTPA nor BOPA derivatives showed radical scavenging properties in H2O2 photolysis, implying that inhibition of the Cu(I)-induced Fenton reaction by both BTPA and BOPA analogues occurred predominantly through Cu(I)-chelation. In addition, NMR-monitored Cu(I)- and Zn(II)-titration of BTPA compounds 8 and 10 showed their high selectivity to a soft metal ion, Cu(I), as compared to a borderline metal ion, Zn(II). In summary, lipophilic BTPA analogues are promising highly selective Cu(I) ion chelators.

Transdermal absorption of memantin--effect of chemical enhancers, iontophoresis, and role of enhancer lipophilicity.

PubMed

del Rio-Sancho, S; Serna-Jiménez, C E; Calatayud-Pascual, M A; Balaguer-Fernández, C; Femenía-Font, A; Merino, V; López-Castellano, A

2012-09-01

The transdermal administration of memantine may have advantages with respect to oral therapy when treating advanced stages of Alzheimer's disease. With the ultimate objective of administrating memantine through a transdermal patch, the absorption of the drug across skin was evaluated by means of in vitro permeation studies. The effect of several chemical enhancers was studied in order to enhance percutaneous absorption of the memantine. The iontophoretic transdermal transport of memantine hydrochloride using a current density of 0.5 mA/cm(2) was also investigated. Results demonstrated that pre-treatment of the skin with R-(+)-limonene, laurocapram, decenoic acid, or oleic acid produced a statistically significant increment in the transdermal flux of memantine hydrochloride with respect to the control. Iontophoresis exhibited the greatest ability to enhance the flux of drug with respect to the control; nevertheless, the results obtained with R-(+)-limonene indicate that this compound could be of great use as a percutaneous enhancer in a memantine transdermal delivery system. In this study, the relationship between enhancement activity and lipophilicity was also studied. Satisfactory correlations have been obtained between the optimum lipophilicity of the enhancer and n-octanol/water partition coefficients of drugs. This relationship is a very useful tool that could allow to reduce time and to optimize the selection of appropriate enhancers for transdermal formulations. Copyright © 2012 Elsevier B.V. All rights reserved.

PEGylation of supercooled smectic cholesteryl myristate nanoparticles.

PubMed

Mengersen, Friederike; Bunjes, Heike

2012-06-01

Supercooled smectic cholesterol ester nanoparticles are under investigation as a new carrier system for lipophilic drugs. The smectic thermotropic liquid crystalline state of the matrix lipid is expected to lead to advantages with respect to physicochemical stability and drug loading capacity. Such nanoparticles can be prepared by high-pressure melt homogenization in the presence of emulsifiers. The purpose of this study was to develop PEGylated supercooled smectic cholesteryl myristate nanoparticles for parenteral administration and to provide evidence of the successful PEGylation by detecting the alterations of particle properties due to the insertion of PEGylated phospholipid into the surface layer of the particles. To achieve PEGylation, MPEG(2000)-DSPE was processed together with the phospholipids used as emulsifiers during particle preparation. The influence of the PEGylated phospholipid on the size, zeta potential, phase behavior and recrystallization tendency of the nanoparticles indicated the insertion of MPEG(2000)-DSPE into the surface layer of the particles. Evidence of the PEGylation was also obtained by (1)H NMR measurements, and the steric stabilization was verified by neutralizing the particle surface charge with calcium chloride or adjusting the pH value. As sterility is an important aspect with regard to parenteral administration of the dispersions their stability upon autoclaving was a further point of interest in the present study. The results indicate that PEGylated particles can be sterilized by autoclaving. In conclusion, the PEGylated particles are a promising formulation with respect to small particle size, stability against recrystallization and upon autoclaving. Copyright © 2012 Elsevier B.V. All rights reserved.

Formulation and development of bicontinuous nanostructured liquid crystalline particles of efavirenz.

PubMed

Avachat, Amelia M; Parpani, Shreekrishna S

2015-02-01

Efavirenz is a lipophilic non-nucleoside reverse transcriptase inhibitor used in the first-line pediatric therapeutic cocktail. Due to its high lipophilicity (logP = 5.4) and poor aqueous solubility (intrinsic water solubility = 8.3 μg/mL) efavirenz has low bioavailability. A 30 mg/mL solution in a medium-chain triglyceride vehicle is the only pediatric formulation available with an oral bioavailability 20% lower than the solid form. The current work was aimed at formulating and characterizing liquid crystal nanoparticles for oral delivery of efavirenz to improve oral bioavailability, provide sustained release, minimize side effects and drug resistance. Formulation of cubosomes was done by two methods; sonication and spray drying. Sonication gave highest entrapment efficiency and least particle size. Further, monoolein was substituted with phytantriol as monoolein gets degraded in the presence of lipase when administered orally with consequent loss of liquid crystalline structure. It was confirmed that there was no difference in particle size, entrapment efficiency and nature of product formed by using monoolein or phytantriol. The best formulation was found to be F9, having particle size 104.19 ± 0.21 nm and entrapment efficiency 91.40 ± 0.10%. In vitro release at the end of 12h was found to be 56.45% and zeta potential to be -23.14 mV which stabilized the cubic phase dispersions. It was further characterized for TEM, small angle X-ray scattering (SAXS), DSC and stability studies. SAXS revealed Pn3m space group, indicating a diamond cubic phase which was further confirmed by TEM. Pharmacokinetics of EFV was studied in male Wistar rats. EFV-loaded cubosome dispersions exhibited 1.93 and 1.62-fold increase in peak plasma concentration (Cmax) and 1.48 and 1.42-fold increase in AUC in comparison to that of a suspension prepared with the contents of EFV capsules suspended in 1.5% carboxymethylcellulose PBS solution (pH 5.0), and an EFV solution in medium-chain triglyceride respectively. Thus, stable cubosomes of efavirenz with increased bioavailability providing sustained release effect could be prepared successfully using phytantriol and poloxamer 407. Copyright © 2014 Elsevier B.V. All rights reserved.

Determination of the variability of both hydrophilic and lipophilic toxins in endemic wild bivalves and carnivorous gastropods from the southern part of Chile.

PubMed

Zamorano, Ruben; Marín, Michelle; Cabrera, Fabiola; Figueroa, Diego; Contreras, Cristóbal; Barriga, Andrés; Lagos, Néstor; García, Carlos

2013-01-01

The aim of this study was to analyse and determine the composition of paralytic shellfish poisoning (PSP) toxins and lipophilic toxins in the Region of Aysén, Chile, in wild endemic mussels (Mytilus chilensis, Venus antiqua, Aulacomya ater, Choromytilus chorus, Tagelus dombeii and Gari solida) and in two endemic carnivorous molluscs species (Concholepas concholepas and Argobuccinum ranelliforme). PSP-toxin contents were determined by using HPLC with fluorescence detection, while lipophilic toxins were determined by using LC-MS/MS. Mean concentrations for the total of PSP toxins were in the range 55-2505 μg saxitoxin-equivalent/100 g. The two most contaminated samples for PSP toxicity were bivalve Gari solida and carnivorous Argobuccinum ranelliforme with 2505 ± 101 and 1850 ± 137 μg saxitoxin-equivalent/100 g, respectively (p < 0.05). The lipophilic toxins identified were okadaic acid, dinophysistoxin-1 (DTX-1), azaspiracid-1 (AZA-1), pectenotoxin-2 (PTX-2) and yessotoxins (YTX). All analysed molluscs contained lipophilic toxins at levels ranging from 56 ± 4.8 to 156.1 ± 8.2 μg of okadaic acid-equivalent/kg shellfish together with YTX at levels ranging from 1.0 ± 0.1 to 18 ± 0.9 μg of YTX-equivalent/kg shellfish and AZA at levels ranging from 3.6 ± 0.2 to 31 ± 2.1 μg of AZA-equivalent/kg shellfish. Furthermore, different bivalves and gastropods differ in their capacity of retention of lipophilic toxins, as shown by the determination of their respective lipophilic toxins levels. In all the evaluated species, the presence of lipophilic toxins associated with biotransformation in molluscs and carnivorous gastropods was not identified, in contrast to the identification of PSP toxins, where the profiles identified in the different species are directly related to biotransformation processes. Thus, this study provides evidence that the concentration of toxins in the food intake of the evaluated species (Bivalvia and Gastropoda class) determines the degree of bioaccumulation and biotransformation they will thereafter exhibit.

Physicochemical and Pharmacological Characterization of Permanently Charged Opioids.

PubMed

Mazak, Karoly; Noszal, Bela; Hosztafi, Sandor

2017-01-01

The main aim of synthesizing permanently charged opioids is to ensure that they do not enter the central nervous system. Such drugs can provide analgesic activity with reduced sedation and other side effects on the central nervous system. We undertook a search of bibliographic databases for peer-reviewed research literature and also summarized our published results in this field. The present review focuses on the characterization of permanently charged opioids by various physicochemical methods, and in vitro as well as in vivo tests. The basicity and lipophilicity of opioid alkaloids are discussed at the microscopic, speciesspecific level. Glucuronide conjugates of opioids are also reviewed. Whereas the primary metabolite morphine-3-glucuronide does not bind to opioid receptors with high affinity, morphine-6-glucuronide is a potent analgesic, at least, partly due to its unexpectedly high lipophilicity. We discuss the quaternary ammonium opioid derivatives of a permanent positive charge, detailing their antinociceptive activity and effects on gastrointestinal motility in various in vivo animal tests and in vitro studies. Compounds with antagonistic activity are also reviewed. The last part of our study concentrates on sulfate conjugates of morphine derivatives that display unique pharmacological properties because they carry a negative charge at any pH value in the human body. In conclusion, the findings of this review confirm the importance of permanently charged opioids in the investigated fields of pharmacology. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

COMPUTER PREDICTION OF BIOLOGICAL ACTIVITY OF DIMETHYL-N-(BENZOYL)AMIDOPHOSPHATE AND DIMETHYL-N-(PHENYLSULFONYL)AMIDOPHOSPHATE, EVALUATION OF THEIR CYTOTOXIC ACTIVITY AGAINST LEUKEMIC CELLS IN VITRO.

PubMed

Grynyuk, I I; Prylutska, S V; Kariaka, N S; Sliva, T Yu; Moroz, O V; Franskevych, D V; Amirkhanov, V M; Matyshevska, O P; Slobodyanik, M S

2015-01-01

Structural analogues of β-diketones--dimethyl-N-(benzoyl)amidophosphate (HCP) and dimethyl-N-(phenylsulfonyl)amidophosphate (HSP) were synthesized and identified by the methods of IR, 1H and 31P NMR spectroscopy. Screening of biological activity and calculation of physicochemical parameters of HCP and HSP compounds were done with the use of PASS and ACD/Labs computer programs. A wide range of biological activity of synthesized compounds, antitumor activity in particular, has been found. Calculations of the bioavailability criteria indicate that the investigated compounds have no deviations from Lipinski's rules. HCP compound is characterized by a high lipophilicity at physiological pH as compared to HSP. It was found that cytotoxic effect of the studied compounds on the leukemic L1210 cells was of time- and dose-dependent character. HCP is characterized by more pronounced and early cytotoxic effects as compared to HSP. It was shown that 2.5 mM HCP increased ROS production 3 times in the early period of incubation, and decreased cell viability by 40% after 48 h, and by 66%--after 72 h. Based on the computer calculation and undertaken research, HCP was selected for target chemical modifications and enhancement of its antitumor effect.

Impacts of compound properties and sediment characteristics on the sorption behaviour of pharmaceuticals in aquatic systems.

PubMed

Al-Khazrajy, Omar S A; Boxall, Alistair B A

2016-11-05

Sorption is a key factor in determining the persistence, attenuation and bioavailability of sediment-associated contaminants. However, our understanding of the sorption behaviour of pharmaceuticals in sediments is poor. In this study, we investigated the sorption behaviour of a diverse set of pharmaceuticals in a range sediment types. Sorption affinity of pharmaceuticals for all sediments was found to increase in the order mefenamic acid

Investigation of the retention/pH profile of zwitterionic fluoroquinolones in reversed-phase and ion-interaction high performance liquid chromatography.

PubMed

Pistos, C; Tsantili-Kakoulidou, A; Koupparis, M

2005-09-15

The retention/pH profiles of three fluoroquinolones, ofloxacin, norfloxacin and ciprofloxacin, was investigated by means of reversed-phase high performance liquid chromatography (RP-HPLC) and reversed-phase ion-interaction chromatography (RP-IIC), using an octadecylsilane stationary phase and acetonitrile as organic modifier. Sodium hexanesulphonate and tetrabutylammonium hydroxide were used as sources of counter ions in ion-interaction chromatography. The retention/pH profiles under in RP-HPLC were compared to the corresponding lipophilicity/pH profiles. Despite the rather hydrophilic nature of the three fluoroquinolones positive retention factors were obtained while there was a shift of the retention maximum towards more acidic pH values. This behavior was attributed mainly to non-hydrophobic silanophilic interactions with the silanized silica gel material of the stationary phase. In ion-interaction chromatography the effect of counter ions over a broad pH range was found to be ruled rather by the ion pair formation in the mobile phase which led to a drastic decrease in retention as a consequence of the disruption of the zwitterionic structure and thereupon the deliberation of a net charge in the molecules. At pH values at which zwitterionic structure was not favored both the ion-exchange and ion pair formation mechanisms were assumed to contribute to the retention.

Physiologically Based Absorption Modeling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Alectinib.

PubMed

Parrott, Neil J; Yu, Li J; Takano, Ryusuke; Nakamura, Mikiko; Morcos, Peter N

2016-11-01

Alectinib, a lipophilic, basic, anaplastic lymphoma kinase (ALK) inhibitor with very low aqueous solubility, has received Food and Drug Administration-accelerated approval for the treatment of patients with ALK+ non-small-cell lung cancer. This paper describes the application of physiologically based absorption modeling during clinical development to predict and understand the impact of food and gastric pH changes on alectinib absorption. The GastroPlus ™ software was used to develop an absorption model integrating in vitro and in silico data on drug substance properties. Oral pharmacokinetics was simulated by linking the absorption model to a disposition model fit to pharmacokinetic data obtained after an intravenous infusion. Simulations were compared to clinical data from a food effect study and a drug-drug interaction study with esomeprazole, a gastric acid-reducing agent. Prospective predictions of a positive food effect and negligible impact of gastric pH elevation were confirmed with clinical data, although the exact magnitude of the food effect could not be predicted with confidence. After optimization of the absorption model with clinical food effect data, a refined model was further applied to derive recommendations on the timing of dose administration with respect to a meal. The application of biopharmaceutical absorption modeling is an area with great potential to further streamline late stage drug development and with impact on regulatory questions.

Rapid-gradient HPLC method for measuring drug interactions with immobilized artificial membrane: comparison with other lipophilicity measures.

PubMed

Valko, K; Du, C M; Bevan, C D; Reynolds, D P; Abraham, M H

2000-08-01

A fast-gradient high-performance liquid chromatographic (HPLC) method has been suggested to characterize the interactions of drugs with an immobilized artificial membrane (IAM). With a set of standards, the gradient retention times can be converted to Chromatographic Hydrophobicity Index values referring to IAM chromatography (CHI(IAM)) that approximates an acetonitrile concentration with which the equal distribution of compound can be achieved between the mobile phase and IAM. The CHI(IAM) values are more suitable for interlaboratory comparison and for high throughput screening of new molecular entities than the log k(IAM) values (isocratic retention factor on IAM). The fast-gradient method has been validated against the isocratic log k(IAM) values using the linear free energy relationship solvation equations based on the data from 48 compounds. The compound set was selected to provide a wide range and the least cross-correlation between the molecular descriptors in the solvation equation: (2) where SP is a solute property (e.g., logarithm of partition coefficients, reversed-phase (RP)-HPLC retention parameters, such as log k, log k(w), etc.) and the explanatory variables are solute descriptors as follows: R(2) is an excess molar refraction that can be obtained from the measured refractive index of a compound, pi(2)(H) is the solute dipolarity/polarizability, summation operatoralpha(2)(H) and summation operatorbeta(2)(0) are the solute overall or effective hydrogen-bond acidity and basicity, respectively, and V(x) is the McGowan characteristic volume (in cm(3)/100 mol) that can be calculated for any solute simply from molecular structure using a table of atomic constants. It was found that the relative constants of the solvation equation were very similar for the CHI(IAM) and for the log k(IAM). The IAM lipophilicity scale was quite similar to the octanol/water lipophilicity scale for neutral compounds. The effect of charge on the interaction with IAM was studied by varying the mobile phase pH. Copyright 2000 Wiley-Liss, Inc.

The influence of natural deep eutectic solvents on bioactive natural products: studying interactions between a hydrogel model and Schisandra chinensis metabolites.

PubMed

Liu, Yang; Zhang, Yu; Chen, Shao-Nong; Friesen, J Brent; Nikolić, Dejan; Choules, Mary P; McAlpine, James B; Lankin, David C; Gemeinhart, Richard A; Pauli, Guido F

2018-06-01

Natural Deep Eutectic Solvent (NADES) species can exhibit unexpected solubilizing power for lipophilic molecules despite their simple composition: hydrophilic organic molecules and water. In the present study, the unique properties of NADES species were applied in combination with a model polymer system: a hydrophilic chitosan/alginate hydrogel. Briefly, NADES species (e.g., mannose-dimethylurea-water, 2:5:5, mole/mole) formed matrices to 1) dissolve lipophilic molecules (e.g., curcumin), 2) load lipophilic molecule(s) into the hydrogel, and 3) spontaneously vacate from the system. NADES species ubiquitously occur in natural sources, and a crude extract is a mixture of the NADES species and bioactive metabolites. Based on these ideas, we hypothesized that the crude extract may also allow the loading of natural bioactive molecules from a natural NADES species into (bio)hydrogel systems. To evaluate this hypothesis in vitro, Schisandra chinensis fruit extract was chosen as a representative mixture of lipophilic botanical molecules and hydrophilic NADES species. The results showed that the NADES matrix of S. chinensis was capable of loading at least three bioactive lignans (i.e., gomisin A, gomisin J, and angeloylgomisin H) into the polymer system. The lipophilic metabolites can subsequently be released from the hydrogel. The outcomes suggest that a unique drug delivery mechanism may exist in nature, thereby potentially improving the bioavailability of lipophilic metabolites through physicochemical interactions with the NADES. Copyright © 2018 Elsevier B.V. All rights reserved.

Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies.

PubMed

Fong, Clifford W

2014-10-06

The atomic electrostatic potentials calculated by the CHELPG method have been shown to be sensitive indicators of the gas phase and solution properties of the statins. Solvation free energies in water, n-octanol and n-octane have been determined using the SMD solvent model. The percentage hydrophilicity and hydrophobicity (or lipophilicity) of the statins in solution have been determined using (a) the differences in solvation free energies between n-octanol and n-octane as a measure of hydrophilicity, and the solvation energy in octane as a measure of hydrophobicity (b) the sum of the atomic electrostatic charges on the hydrogen bonding and polar bonding nuclei of the common pharmacophore combined with a solvent measure of hydrophobicity, and (c) using the buried surface areas after statin binding to HMGCR to calculate the hydrophobicity of the bound statins. The data suggests that clinical definitions of statins as either "hydrophilic" or "lipophilic" based on experimental partition coefficients are misleading. An estimate of the binding energy between rosuvastatin and HMGCR has been made using: (a) a coulombic electrostatic interaction model, (b) the calculated desolvation and resolvation of the statin in water, and (c) the first shell transfer solvation energy as a proxy for the restructuring of the water molecules immediately adjacent to the active binding site of HMGCR prior to binding. Desolvation and resolvation of the statins before and after binding to HMGCR are major determinants of the energetics of the binding process. An analysis of the amphiphilic nature of lovastatin anion, acid and lactone and fluvastatin anion and their abilities to cross the blood brain barrier has indicated that this process may be dominated by desolvation and resolvation effects, rather than the statin molecular size or statin-lipid interactions within the bilayer. The ionization energy and electron affinity of the statins are sensitive physical indicators of the ease that the various statins can undergo endogenous oxidative metabolism. The absolute chemical hardness is also an indicator of the stability of the statins, and may be a useful indicator for drug design. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

An acidic pH independent piperazine–TPE AIEgen as a unique bioprobe for lysosome tracing† †Electronic supplementary information (ESI) available: NMR, single crystal X-ray crystallography of PIP–TPE, live cell and fixed cell fluorescence imaging, MTT, photostability, and theoretical calculations. CCDC 1555412. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7sc03515b

PubMed Central

Cai, Yuanjing; Gui, Chen; Samedov, Kerim; Su, Huifang; Gu, Xinggui; Li, Shiwu; Luo, Wenwen; Sung, Herman H. Y.; Lam, Jacky W. Y.; Kwok, Ryan T. K.; Williams, Ian D.

2017-01-01

Lysosomes are involved in a multitude of cellular processes and their dysfunction is associated with various diseases. They are the most acidic organelles (pH 3.8–6.6, size 0.1–1.2 μm) with the highest viscosity (47–190 cP at 25 °C) in the cell. Because of their acidity, pH dependent non-AIE active fluorescent lysosomal probes have been developed that rely on protonation inhibited photoinduced electron transfer (PET). In this work, an acidic pH independent lysosome targetable piperazine–TPE (PIP–TPE) AIEgen has been designed with unique photophysical properties making it a suitable probe for quantifying viscosity. In a non-aggregated state PIP–TPE shows deep-blue emission as opposed to its yellowish-green emission in the bulk. It possesses high specificity for lysosomes with negligible cytotoxicity and good tracing ability due to its better photostability compared to LysoTracker Red. In contrast to most known lysosome probes that rely solely on PET, restriction of intramolecular motion (RIM) due to the larger viscosity inside the lysosomes is the mechanism responsible for PIP–TPE’s fluorescence. PIP–TPE’s high selectivity is attributed to its unique molecular design that features piperazine fragments providing a perfect balance between lipophilicity and polarity. PMID:29568423

Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy.

PubMed

Hansen, Steffen V F; Christiansen, Elisabeth; Urban, Christian; Hudson, Brian D; Stocker, Claire J; Due-Hansen, Maria E; Wargent, Ed T; Shimpukade, Bharat; Almeida, Reinaldo; Ejsing, Christer S; Cawthorne, Michael A; Kassack, Matthias U; Milligan, Graeme; Ulven, Trond

2016-03-24

The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.

Implications of the stability behavior of zinc oxide nanoparticles for toxicological studies

NASA Astrophysics Data System (ADS)

Meißner, Tobias; Oelschlägel, Kathrin; Potthoff, Annegret

2014-08-01

The increasing use of zinc oxide (ZnO) nanoparticles in sunscreens and other cosmetic products demands a risk assessment that has to be done in toxicological studies. Such investigations require profound knowledge of the behavior of ZnO in cell culture media. The current study was performed to get well-dispersed suspensions of a hydrophilic (ZnO-hydro) and a lipophilic coated (ZnO-lipo) ZnO nanomaterial for use in in vitro tests. Therefore, systematic tests were carried out with common dispersants (phosphate, lecithin, proteins) to elucidate chemical and physical changes of ZnO nanoparticles in water and physiological solutions (PBS, DMEM). Non-physiological stock suspensions were prepared using ultrasonication. Time-dependent changes of pH, conductivity, zeta potential, particle size and dissolution were recorded. Secondly, the stock suspensions were added to physiological media with or without albumin (BSA) or serum (FBS), to examine characteristics such as agglomeration and dissolution. Stable stock suspensions were obtained using phosphate as natural and physiological electrostatic stabilizing agent. Lecithin proved to be an effective wetting agent for ZnO-lipo. Although the particle size remained constant, the suspension changed over time. The pH increased as a result of ZnO dissolution and formation of zinc phosphate complexes. The behavior of ZnO in physiological media was found to depend strongly on the additives used. Applying only phosphate as additive, ZnO-hydro agglomerated within minutes. In the presence of lecithin or BSA/serum, agglomeration was inhibited. ZnO dissolution was higher under physiological conditions than in the stock suspension. Serum especially promoted this process. Using body-related dispersants (phosphate, lecithin) non-agglomerating stock suspensions of hydrophilic and lipophilic ZnO were prepared as a prerequisite to perform meaningful toxicological investigation. Both nanomaterials showed a non-negligible dissolution behavior that strongly depended on the surrounding conditions. Agglomeration of ZnO particles in physiological media is a complex function of particle coating, used dispersants and serum proteins if supplemented. The present study gives a clear guideline how to prepare and handle suspensions with ZnO for in vitro testing and allows the correlation between the chemical-physical particles behavior with findings from toxicological tests.

Formulation and in vitro release evaluation of newly synthesized palm kernel oil esters-based nanoemulsion delivery system for 30% ethanolic dried extract derived from local Phyllanthus urinaria for skin antiaging.

PubMed

Mahdi, Elrashid Saleh; Noor, Azmin Mohd; Sakeena, Mohamed Hameem; Abdullah, Ghassan Z; Abdulkarim, Muthanna F; Sattar, Munavvar Abdul

2011-01-01

Recently there has been a remarkable surge of interest about natural products and their applications in the cosmetic industry. Topical delivery of antioxidants from natural sources is one of the approaches used to reverse signs of skin aging. The aim of this research was to develop a nanoemulsion cream for topical delivery of 30% ethanolic extract derived from local Phyllanthus urinaria (P. urinaria) for skin antiaging. Palm kernel oil esters (PKOEs)-based nanoemulsions were loaded with P. urinaria extract using a spontaneous method and characterized with respect to particle size, zeta potential, and rheological properties. The release profile of the extract was evaluated using in vitro Franz diffusion cells from an artificial membrane and the antioxidant activity of the extract released was evaluated using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) method. Formulation F12 consisted of wt/wt, 0.05% P. urinaria extract, 1% cetyl alcohol, 0.5% glyceryl monostearate, 12% PKOEs, and 27% Tween 80/Span 80 (9/1) with a hydrophilic lipophilic balance of 13.9, and a 59.5% phosphate buffer system at pH 7.4. Formulation F36 was comprised of 0.05% P. urinaria extract, 1% cetyl alcohol, 1% glyceryl monostearate, 14% PKOEs, 28% Tween 80/Span 80 (9/1) with a hydrophilic lipophilic balance of 13.9, and 56% phosphate buffer system at pH 7.4 with shear thinning and thixotropy. The droplet size of F12 and F36 was 30.74 nm and 35.71 nm, respectively, and their nanosizes were confirmed by transmission electron microscopy images. Thereafter, 51.30% and 51.02% of the loaded extract was released from F12 and F36 through an artificial cellulose membrane, scavenging 29.89% and 30.05% of DPPH radical activity, respectively. The P. urinaria extract was successfully incorporated into a PKOEs-based nanoemulsion delivery system. In vitro release of the extract from the formulations showed DPPH radical scavenging activity. These formulations can neutralize reactive oxygen species and counteract oxidative injury induced by ultraviolet radiation and thereby ameliorate skin aging.

Transdermal permeation of drugs with differing lipophilicity: Effect of penetration enhancer camphor.

PubMed

Xie, Feng; Chai, Jia-Ke; Hu, Quan; Yu, Yong-Hui; Ma, Li; Liu, Ling-Ying; Zhang, Xu-Long; Li, Bai-Ling; Zhang, Dong-Hai

2016-06-30

The aim of the present study was to investigate the potential application of (+)-camphor as a penetration enhancer for the transdermal delivery of drugs with differing lipophilicity. The skin irritation of camphor was evaluated by in vitro cytotoxicity assays and in vivo transdermal water loss (TEWL) measurements. A series of model drugs with a wide span of lipophilicity (logP value ranging from 3.80 to -0.95), namely indometacin, lidocaine, aspirin, antipyrine, tegafur and 5-fluorouracil, were tested using in vitro transdermal permeation experiments to assess the penetration-enhancing profile of camphor. Meanwhile, the in vivo skin microdialysis was carried out to further investigate the enhancing effect of camphor on the lipophilic and hydrophilic model drugs (i.e. lidocaine and tegafur). SC (stratum corneum)/vehicle partition coefficient and Fourier transform infrared spectroscopy (FTIR) were performed to probe the regulation action of camphor in the skin permeability barrier. It was found that camphor produced a relatively low skin irritation, compared with the frequently-used and standard penetration enhancer laurocapram. In vitro skin permeation studies showed that camphor could significantly facilitate the transdermal absorption of model drugs with differing lipophilicity, and the penetration-enhancing activities were in a parabola curve going downwards with the drug logP values, which displayed the optimal penetration-enhancing efficiency for the weak lipophilic or hydrophilic drugs (an estimated logP value of 0). In vivo skin microdialysis showed that camphor had a similar penetration behavior on transdermal absorption of model drugs. Meanwhile, the partition of lipophilic drugs into SC was increased after treatment with camphor, and camphor also produced a shift of CH2 vibration of SC lipid to higher wavenumbers and decreased the peak area of the CH2 vibration, probably resulting in the alteration of the skin permeability barrier. This suggests that camphor might be a safe and effective penetration enhancer for transdermal drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Analysis of lipophilic pigments from a phototrophic microbial mat community by high performance liquid chromatography

NASA Technical Reports Server (NTRS)

Palmisano, A. C.; Cronin, S. E.; Des Marais, D. J.

1988-01-01

As assay for lipophilic pigments in phototrophic microbial mat communities using reverse phase-high performance liquid chromatography was developed which allows the separation of 15 carotenoids and chloropigments in a single 30 min program. Lipophilic pigments in a laminated mat from a commercial salina near Laguna Guerrero Negro, Baja California Sur, Mexico reflected their source organisms. Myxoxanthophyll, echinenone, canthaxanthin, and zeaxanthin were derived from cyanobacteria; chlorophyll c, and fucoxanthin from diatoms; chlorophyll a from cyanobacteria and diatoms; bacteriochlorophylls a and c, bacteriophaeophytin a, and gamma-carotene from Chloroflexus spp.; and beta-carotene from a variety of phototrophs. Sensitivity of detection was 0.6-6.1 ng for carotenoids and 1.7-12 ng for most chloropigments. This assay represents a significant improvement over previous analyses of lipophilic pigments in microbial mats and promises to have a wider application to other types of phototrophic communities.

[Study on the dynamic model with supercritical CO2 fluid extracting the lipophilic components in Panax notoginseng].

PubMed

Duan, Xian-Chun; Wang, Yong-Zhong; Zhang, Jun-Ru; Luo, Huan; Zhang, Heng; Xia, Lun-Zhu

2011-08-01

To establish a dynamics model for extracting the lipophilic components in Panax notoginseng with supercritical carbon dioxide (CO2). Based on the theory of counter-flow mass transfer and the molecular mass transfer between the material and the supercritical CO2 fluid under differential mass-conservation equation, a dynamics model was established and computed to compare forecasting result with the experiment process. A dynamics model has been established for supercritical CO2 to extract the lipophilic components in Panax notoginseng, the computed result of this model was consistent with the experiment process basically. The supercritical fluid extract dynamics model established in this research can expound the mechanism in the extract process of which lipophilic components of Panax notoginseng dissolve the mass transfer and is tallied with the actual extract process. This provides certain instruction for the supercritical CO2 fluid extract' s industrialization enlargement.

Amphiphilic naproxen prodrugs: differential scanning calorimetry study on their interaction with phospholipid bilayers.

PubMed

Giuffrida, Maria Chiara; Pignatello, Rosario; Castelli, Francesco; Sarpietro, Maria Grazia

2017-09-01

Naproxen, a nonsteroid anti-inflammatory drug studied for Alzheimer's disease, was conjugated with lipoamino acids (LAA) directly or through a diethylamine (EDA) spacer to improve the drug lipophilicity and the interaction with phospholipid bilayers. The interaction of naproxen and its prodrugs with biomembrane models consisting of dimyristoylphosphatidylcholine multilamellar vesicles was studied by differential scanning calorimetry. The transfer of prodrugs from a lipophilic carrier to a biomembrane model was also studied. Naproxen conjugation to lipoamino acids improves its interaction with biomembrane models and affects the transfer from a lipophilic carrier to biomembrane model. LAA portion may localize between the phospholipid chains; the entity of the interaction depends not only on the presence of the spacer but also on the LAA chain length. Variation of LAA portion can modulate the naproxen prodrugs affinity towards the biological membrane as well as towards the lipophilic carrier. © 2017 Royal Pharmaceutical Society.

Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury.

PubMed

McEuen, Kristin; Borlak, Jürgen; Tong, Weida; Chen, Minjun

2017-06-22

Drug-induced liver injury (DILI), although rare, is a frequent cause of adverse drug reactions resulting in warnings and withdrawals of numerous medications. Despite the research community's best efforts, current testing strategies aimed at identifying hepatotoxic drugs prior to human trials are not sufficiently powered to predict the complex mechanisms leading to DILI. In our previous studies, we demonstrated lipophilicity and dose to be associated with increased DILI risk and, and in our latest work, we factored reactive metabolites into the algorithm to predict DILI. Given the inconsistency in determining the potential for drugs to cause DILI, the present study comprehensively assesses the relationship between DILI risk and lipophilicity and the extent of metabolism using a large published dataset of 1036 Food and Drug Administration (FDA)-approved drugs by considering five independent DILI annotations. We found that lipophilicity and the extent of metabolism alone were associated with increased risk for DILI. Moreover, when analyzed in combination with high daily dose (≥100 mg), lipophilicity was statistically significantly associated with the risk of DILI across all datasets ( p < 0.05). Similarly, the combination of extensive hepatic metabolism (≥50%) and high daily dose (≥100 mg) was also strongly associated with an increased risk of DILI among all datasets analyzed ( p < 0.05). Our results suggest that both lipophilicity and the extent of hepatic metabolism can be considered important risk factors for DILI in humans, and that this relationship to DILI risk is much stronger when considered in combination with dose. The proposed paradigm allows the convergence of different published annotations to a more uniform assessment.

Effect of molecular characteristics on cellular uptake, subcellular localization, and phototoxicity of Zn(II) N-alkylpyridylporphyrins.

PubMed

Ezzeddine, Rima; Al-Banaw, Anwar; Tovmasyan, Artak; Craik, James D; Batinic-Haberle, Ines; Benov, Ludmil T

2013-12-20

Tetra-cationic Zn(II) meso-tetrakis(N-alkylpyridinium-2 (or -3 or -4)-yl)porphyrins (ZnPs) with progressively increased lipophilicity were synthesized to investigate how the tri-dimensional shape and lipophilicity of the photosensitizer (PS) affect cellular uptake, subcellular distribution, and photodynamic efficacy. The effect of the tri-dimensional shape of the molecule was studied by shifting the N-alkyl substituent attached to the pyridyl nitrogen from ortho to meta and para positions. Progressive increase of lipophilicity from shorter hydrophilic (methyl) to longer amphiphilic (hexyl) alkyl chains increased the phototoxicity of the ZnP PSs. PS efficacy was also increased for all derivatives when the alkyl substituents were shifted from ortho to meta, and from meta to para positions. Both cellular uptake and subcellular distribution of the PSs were affected by the lipophilicity and the position of the alkyl chains on the periphery of the porphyrin ring. Whereas the hydrophilic ZnPs demonstrated mostly lysosomal distribution, the amphiphilic hexyl derivatives were associated with mitochondria, endoplasmic reticulum, and plasma membrane. A comparison of hexyl isomers revealed that cellular uptake and partition into membranes followed the order para > meta > ortho. Varying the position and length of the alkyl substituents affects (i) the exposure of cationic charges for electrostatic interactions with anionic biomolecules and (ii) the lipophilicity of the molecule. The charge, lipophilicity, and the tri-dimensional shape of the PS are the major factors that determine cellular uptake, subcellular distribution, and as a consequence, the phototoxicity of the PSs.

Effect of Molecular Characteristics on Cellular Uptake, Subcellular Localization, and Phototoxicity of Zn(II) N-Alkylpyridylporphyrins*

PubMed Central

Ezzeddine, Rima; Al-Banaw, Anwar; Tovmasyan, Artak; Craik, James D.; Batinic-Haberle, Ines; Benov, Ludmil T.

2013-01-01

Tetra-cationic Zn(II) meso-tetrakis(N-alkylpyridinium-2 (or -3 or -4)-yl)porphyrins (ZnPs) with progressively increased lipophilicity were synthesized to investigate how the tri-dimensional shape and lipophilicity of the photosensitizer (PS) affect cellular uptake, subcellular distribution, and photodynamic efficacy. The effect of the tri-dimensional shape of the molecule was studied by shifting the N-alkyl substituent attached to the pyridyl nitrogen from ortho to meta and para positions. Progressive increase of lipophilicity from shorter hydrophilic (methyl) to longer amphiphilic (hexyl) alkyl chains increased the phototoxicity of the ZnP PSs. PS efficacy was also increased for all derivatives when the alkyl substituents were shifted from ortho to meta, and from meta to para positions. Both cellular uptake and subcellular distribution of the PSs were affected by the lipophilicity and the position of the alkyl chains on the periphery of the porphyrin ring. Whereas the hydrophilic ZnPs demonstrated mostly lysosomal distribution, the amphiphilic hexyl derivatives were associated with mitochondria, endoplasmic reticulum, and plasma membrane. A comparison of hexyl isomers revealed that cellular uptake and partition into membranes followed the order para > meta > ortho. Varying the position and length of the alkyl substituents affects (i) the exposure of cationic charges for electrostatic interactions with anionic biomolecules and (ii) the lipophilicity of the molecule. The charge, lipophilicity, and the tri-dimensional shape of the PS are the major factors that determine cellular uptake, subcellular distribution, and as a consequence, the phototoxicity of the PSs. PMID:24214973

Rapid and Efficient Conversion of All-E-astaxanthin to 9Z- and 13Z-Isomers and Assessment of Their Stability and Antioxidant Activities.

PubMed

Yang, Cheng; Zhang, Lianfu; Zhang, Hua; Sun, Qingrui; Liu, Ronghua; Li, Jing; Wu, Leiyan; Tsao, Rong

2017-02-01

An optimized isomerization method was developed by heating all-E-astaxanthin in ethyl acetate (70 °C) with I-TiO 2 catalyst, yielding 22.7% and 16.9% of 9Z- and 13Z-astaxanthin, respectively, in 2 h, with 92-95% purity after semipreparative HPLC purification. 13Z-Astaxanthin had higher antioxidant activity than all-E- and 9Z-astaxanthins in oxygen radical absorbing capacity assay for lipophilic compounds, photochemiluminescence, and cellular antioxidant activity (CAA) assays, and 9Z-astaxanthin was higher in DPPH radical-scavenging activity assay and lower in CAA assay. All isomers were relatively stable between pH 2.0 and 11.6, except 13Z- and 9Z-astaxanthins at pH 2.0, suggesting they may be converted after passing the gastric phase in vivo. Metal ions did not significantly (p < 0.05) affect the stability. Results of the current study provides a means for further study into the mechanisms related to in vivo transformation and bioavailability of Z-astaxanthins, and their application in the development of functional foods and nutraceutical products.

Agonist-induced PIP(2) hydrolysis inhibits cortical actin dynamics: regulation at a global but not at a micrometer scale.

PubMed

van Rheenen, Jacco; Jalink, Kees

2002-09-01

Phosphatidylinositol 4, 5-bisphosphate (PIP(2)) at the inner leaflet of the plasma membrane has been proposed to locally regulate the actin cytoskeleton. Indeed, recent studies that use GFP-tagged pleckstrin homology domains (GFP-PH) as fluorescent PIP(2) sensors suggest that this lipid is enriched in membrane microdomains. Here we report that this concept needs revision. Using three distinct fluorescent GFP-tagged pleckstrin homology domains, we show that highly mobile GFP-PH patches colocalize perfectly with various lipophilic membrane dyes and, hence, represent increased lipid content rather than PIP(2)-enriched microdomains. We show that bright patches are caused by submicroscopical folds and ruffles in the membrane that can be directly visualized at approximately 15 nm axial resolution with a novel numerically enhanced imaging method. F-actin motility is inhibited significantly by agonist-induced PIP(2) breakdown, and it resumes as soon as PIP(2) levels are back to normal. Thus, our data support a role for PIP(2) in the regulation of cortical actin, but they challenge a model in which spatial differences in PIP(2) regulation of the cytoskeleton exist at a micrometer scale.

Drug release studies from lipid nanoparticles in physiological media by a new DSC method.

PubMed

Roese, Elin; Bunjes, Heike

2017-06-28

Lipid nanoparticles are an interesting parenteral delivery system for poorly water-soluble drugs. In order to approach physiological conditions when conducting release studies from such systems the release media should preferentially contain lipophilic acceptor compartments such as lipoproteins or other colloidal lipophilic components. In practice, drug release studies under such close to physiological conditions may be complicated by the small size of lipid nanoparticles, which is in the same range as that of the potential acceptor particles. This study describes a novel differential scanning calorimetry (DSC) method for drug release measurements which works without separation of donor and acceptor particles. The technique is based on measuring the crystallization temperature of trimyristin nanoparticles by DSC. The crystallization temperature of the nanoparticles decreases proportionally with the amount of active ingredient incorporated and thus increases as a result of drug release. Liquid trimyristin nanoparticles loaded with fenofibrate, orlistat, tocopherol acetate and ubidecarenone were studied in three different release media with increasing complexity and comparability to physiological conditions: a rapeseed oil nanoemulsion, porcine serum and porcine blood. Using the new method, a correlation between release behavior and drug lipophilicity was observed: the higher the logP value of the drug, the slower the release. The extent of drug release was influenced by partition equilibrium as indicated by increased drug release in the rapeseed oil nanoemulsion compared to porcine serum and blood. Copyright © 2017 Elsevier B.V. All rights reserved.

Allelopathic Monoterpenes Interfere with Arabidopsis thaliana Cuticular Waxes and Enhance Transpiration

PubMed Central

Kussmann, Petra; Knop, Mona; Kriegs, Bettina; Gresens, Frank; Eichert, Thomas; Ulbrich, Andreas; Marx, Friedhelm; Fabricius, Heinz; Goldbach, Heiner; Noga, Georg

2007-01-01

Exposure to the allelopathic monoterpenes camphor (100 mg/10 L) and menthol (50 mg/10 L) for 24 h enhanced transpiration of Arabidopsis thaliana fully developed rosette leaves similar to de-waxing. As ascertained by ESEM analyses the leaf surfaces were spotted with platelet like structures which seem to be partly mixed with the lipophilic epicuticular layers. The structures are supposed to contain the condensed monoterpenes, which could be identified by GC. Long term exposure (more than 48 h) to 100 mg/50 mg killed the plants by desiccation, a 24 h exposure caused necrotic spots that became visible one to two days after the treatment. Examinations of the stomatal apertures indicated that monoterpenes induced stomatal opening followed by extreme swelling and a final break down of the protoplasts. Exposure of Arabidopsis thaliana to volatiles of Mentha piperita, Lavandula latifolia and Artemisia camphorata resulted in a dramatic increase of the stomata aperture but swelling of the protoplasts was less exhibited. In contrast to de-waxing, expression of the fatty acid condensing enzyme encoding CER6 gene and de novo synthesis of CER6 protein was not induced after 24 h of exposure to the monoterpenes. The aim of the study was to demonstrate that the lipophilic layers of the leaf surface and the stomata are primary targets of monoterpene allelopathic attack. Enhanced transpiration results from a combination of affected lipophilic wax layers and a disturbed stomata function. PMID:19516993

Synthesis and evaluation of novel 18 F-labeled quinazoline derivatives with low lipophilicity for tumor PET imaging.

PubMed

Chong, Yan; Chang, Jin; Zhao, Wenwen; He, Yong; Li, Yuqiao; Zhang, Huabei; Qi, Chuanmin

2018-02-01

Four novel 18 F-labeled quinazoline derivatives with low lipophilicity, [ 18 F]4-(2-fluoroethoxy)-6,7-dimethoxyquinazoline ([ 18 F]I), [ 18 F]4-(3-((4-(2-fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine ([ 18 F]II), [ 18 F]4-(2-fluoroethoxy)-7-methoxy-6-(2-methoxyethoxy)quinazoline ([ 18 F]III), and [ 18 F]4-(2-fluoroethoxy)-6,7-bis(2-methoxyethoxy)quinazoline ([ 18 F]IV), were synthesized via a 2-step radiosynthesis procedure with an overall radiochemical yield of 10% to 38% (without decay correction) and radiochemical purities of >98%. The lipophilicity and stability of labeled compounds were tested in vitro. The log P values of the 4 radiotracers ranged from 0.52 to 1.07. We then performed ELISA to measure their affinities to EGFR-TK; ELISA assay results indicated that each inhibitor was specifically bounded to EGFR-TK in a dose-dependent manner. The EGFR-TK autophosphorylation IC 50 values of [ 18 F]I, [ 18 F]II, [ 18 F]III, and [ 18 F]IV were 7.732, 0.4698, 0.1174, and 0.1176 μM, respectively. All labeled compounds were evaluated via cellular uptake and blocking studies in HepG2 cell lines in vitro. Cellular uptake and blocking experiment results indicated that [ 18 F]I and [ 18 F]III had excellent cellular uptake at 120-minute postinjection in HepG2 carcinoma cells (51.80 ± 3.42%ID/mg protein and 27.31 ± 1.94%ID/mg protein, respectively). Additionally, biodistribution experiments in S180 tumor-bearing mice in vivo indicated that [ 18 F]I had a very fast clearance in blood and a relatively high uptake ratio of tumor to blood (4.76) and tumor to muscle (1.82) at 60-minute postinjection. [ 18 F]III had a quick clearance in plasma, and its highest uptake ratio of tumor to muscle was 2.55 at 15-minute postinjection. These experimental results and experiences were valuable for the further exploration of novel radiotracers of quinazoline derivatives. Copyright © 2017 John Wiley & Sons, Ltd.

N(G)-Acyl-argininamides as NPY Y(1) receptor antagonists: Influence of structurally diverse acyl substituents on stability and affinity.

PubMed

Weiss, Stefan; Keller, Max; Bernhardt, Günther; Buschauer, Armin; König, Burkhard

2010-09-01

N(G)-Acylated argininamides, covering a broad range of lipophilicity (calculated logD values: -1.8-12.5), were synthesized and investigated for NPY Y(1) receptor (Y(1)R) antagonism, Y(1)R affinity and stability in buffer (N(G)-deacylation, yielding BIBP 3226). Broad structural variation of substituents was tolerated. The K(i) (binding) and K(b) values (Y(1)R antagonism) varied from low nM to one-digit muM. Most of the compounds proved to be sufficiently stable at pH 7.4 over 90min to determine reliable pharmacological data in vitro. Exceptionally high instability was detected when a succinyl moiety was attached to the guanidine, probably, due to an intramolecular cleavage mechanism. Copyright 2010 Elsevier Ltd. All rights reserved.

"Cut-off" effect of antioxidants and/or probes of variable lipophilicity in microheterogeneous media.

PubMed

Aliaga, Carolina; López de Arbina, Amaia; Rezende, Marcos Caroli

2016-09-01

The activities of two hydrophilic (ascorbic acid and Trolox) and two hydrophobic (α-tocopherol and BHT) antioxidants were measured by reaction with a series of 4-alkanoyloxyTEMPO radical probes 1 in buffered (pH 7), aqueous, micellar solutions of reduced Triton-X 100. In all cases, a cut-off effect was observed, in line with previous observations of the same effect for the partitioning of probe series 1 in this medium. These results support an interpretation of the cut-off effect in food emulsions, based on the "amphiphobic" nature of either the antioxidants or probes: competition between two molecular moieties, for the micellar hydrophobic core, tends to expose a reacting fragment differently to a more hydrophilic microenvironment, as the probe or antioxidant hydrophobicity increases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lipophilic extracts from banana fruit residues: a source of valuable phytosterols.

PubMed

Oliveira, Lúcia; Freire, Carmen S R; Silvestre, Armando J D; Cordeiro, Nereida

2008-10-22

The chemical composition of the lipophilic extracts of unripe pulp and peel of banana fruit 'Dwarf Cavendish' was studied by gas chromatography-mass spectrometry. Fatty acids, sterols, and steryl esters are the major families of lipophilic components present in banana tissues, followed by diacylglycerols, steryl glucosides, long chain fatty alcohols, and aromatic compounds. Fatty acids are more abundant in the banana pulp (29-90% of the total amount of lipophilic extract), with linoleic, linolenic, and oleic acids as the major compounds of this family. In banana peel, sterols represent about 49-71% of the lipophilic extract with two triterpenic ketones (31-norcyclolaudenone and cycloeucalenone) as the major components. The detection of high amounts of steryl esters (469-24405 mg/kg) and diacylglycerols (119-878 mg/kg), mainly present in the banana peel extract, explains the increase in the abundance of fatty acids and sterols after alkaline hydrolysis. Several steryl glucosides were also found in significative amounts (273-888 mg/kg), particularly in banana pulp (888 mg/kg). The high content of sterols (and their derivatives) in the 'Dwarf Cavendish' fruit can open new strategies for the valorization of the banana residues as a potential source of high-value phytochemicals with nutraceutical and functional food additive applications.

Effect of lipophilicity on microneedle-mediated iontophoretic transdermal delivery across human skin in vitro.

PubMed

Pawar, Kasturi R; Smith, Forrest; Kolli, Chandra Sekhar; Babu, R Jayachandra

2013-10-01

The effect of lipophilicity of drug on the microneedle (MN)-mediated iontophoretic delivery across dermatomed human skin was studied. Beta blockers with similar pKa but varied log P values were selected as model drugs in this study. Iontophoresis (ITP) or MNs, when used independently, increased the transdermal flux of beta blockers as compared with passive delivery (PD). ITP across the MN-treated skin (MN + ITP) increased the permeation rate of all beta blockers as compared with PD (p < 0.001). The enhancement ratios (ER) for hydrophilic molecules (atenolol and sotalol) were 71- and 78-fold higher for ITP + MN as compared with PD. However, for lipophilic molecule such as propranolol, there was 10-fold increase in the ER as compared with PD. These observations were further substantiated by the skin retention data; an inverse relationship between the skin retention and the hydrophilicity of the drug was observed. The results in the present study point out that the lipophilicity of the molecule plays a significant role on the electrically assisted transdermal delivery of drugs across the microporated skin. Using the combination of ITP + MN, hydrophilic drugs (atenolol and sotalol) were delivered at a much higher rate as compared with lipophilic molecules (propranolol and acebutolol). © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Evaluating the Effect of Peptoid Lipophilicity on Antimicrobial Potency, Cytotoxicity, and Combinatorial Library Design.

PubMed

Turkett, Jeremy A; Bicker, Kevin L

2017-04-10

Growing prevalence of antibiotic resistant bacterial infections necessitates novel antimicrobials, which could be rapidly identified from combinatorial libraries. We report the use of the peptoid library agar diffusion (PLAD) assay to screen peptoid libraries against the ESKAPE pathogens, including the optimization of assay conditions for each pathogen. Work presented here focuses on the tailoring of combinatorial peptoid library design through a detailed study of how peptoid lipophilicity relates to antibacterial potency and mammalian cell toxicity. The information gleaned from this optimization was then applied using the aforementioned screening method to examine the relative potency of peptoid libraries against Staphylococcus aureus, Acinetobacter baumannii, and Enterococcus faecalis prior to and following functionalization with long alkyl tails. The data indicate that overall peptoid hydrophobicity and not simply alkyl tail length is strongly correlated with mammalian cell toxicity. Furthermore, this work demonstrates the utility of the PLAD assay in rapidly evaluating the effect of molecular property changes in similar libraries.

Effects of Different Lipophilized Ferulate Esters in Fish Oil-Enriched Milk: Partitioning, Interaction, Protein, and Lipid Oxidation.

PubMed

Qiu, Xujian; Jacobsen, Charlotte; Villeneuve, Pierre; Durand, Erwann; Sørensen, Ann-Dorit Moltke

2017-11-01

Antioxidant effects of ferulic acid and lipophilized ferulate esters were investigated in fish oil-enriched milk. Methyl ferulate (C1) and ethyl ferulate (C2) more efficiently prevented lipid oxidation than dodecyl ferulate (C12) did, followed by ferulic acid (C0). The combination of C1 or C2 with C12 could have a "synergistic" effect indicated by peroxide value, hexanal, and 1-penten-3-ol analysis results. These antioxidants also showed protein oxidation inhibition effects. The most effective antioxidants (C1 and C2) had the highest concentration in the precipitate phase but the lowest concentration in the aqueous phase, which was the opposite of the partitioning of C0. C12 had the highest concentration in the oil and emulsion phase. In particular, the interaction between ferulates esterified with short and medium alkyl chain lengths could lead to their "synergistic" effects in fish oil-enriched milk, which could be caused by the change in their partitioning or localization at the interface.

Binding of Sudan II and IV to lecithin liposomes and E. coli membranes: insights into the toxicity of hydrophobic azo dyes

PubMed Central

Li, Lu; Gao, Hong-Wen; Ren, Jiao-Rong; Chen, Ling; Li, Yu-Cheng; Zhao, Jian-Fu; Zhao, He-Ping; Yuan, Yuan

2007-01-01

Background Sudan red compounds are hydrophobic azo dyes, still used as food additives in some countries. However, they have been shown to be unsafe, causing tumors in the liver and urinary bladder in rats. They have been classified as category 3 human carcinogens by the International Agency for Research on Cancer. A number of hypotheses that could explain the mechanism of carcinogenesis have been proposed for dyes similar to the Sudan red compounds. Traditionally, investigations of the membrane toxicity of organic substances have focused on hydrocarbons, e.g. polycyclic aromatic hydrocarbons (PAHs), and DDT. In contrast to hydrocarbons, Sudan red compounds contain azo and hydroxy groups, which can form hydrogen bonds with the polar head groups of membrane phospholipids. Thus, entry may be impeded. They could have different toxicities from other lipophilic hydrocarbons. The available data show that because these compounds are lipophilic, interactions with hydrophobic parts of the cell are important for their toxicity. Lipophilic compounds accumulate in the membrane, causing expansion of the membrane surface area, inhibition of primary ion pumps and increased proton permeability. Results This work investigated the interactions of the amphiphilic compounds Sudan II and IV with lecithin liposomes and live Escherichia coli (E. coli). Sudan II and IV binding to lecithin liposomes and live E. coli corresponds to the Langmuir adsorption isotherm. In the Sudan red compounds – lecithin liposome solutions, the binding ratio of Sudan II to lecithin is 1/31 and that of Sudan IV to 1/314. The binding constant of the Sudan II-lecithin complex is 1.75 × 104 and that of the Sudan IV-lecithin complex 2.92 × 105. Besides, the influences of pH, electrolyte and temperature were investigated and analyzed quantitatively. In the Sudan red compounds – E.coli mixture, the binding ratios of Sudan II and Sudan IV to E.coli membrane phospholipid are 1/29 and 1/114. The binding constants of the Sudan II – and Sudan IV- E.coli membrane phospholipid complexes are 1.86 × 104 and 6.02 × 104. Over 60% of Sudan II and 75% of Sudan IV penetrated into E.coli, in which 90% of them remained in the E.coli membrane. Conclusion Experiments of Sudan II and IV binding to lecithin liposomes and live E. coli indicates that amphiphilic compounds may besequestered in thelecithin liposomes and membrane phospholipid bilayer according to the Langmuir adsorption law. Penetration into the cytosol was impeded and inhibited for Sudan red compounds. It is possible for such compounds themselves (excluding their metabolites and by-products)not result directly in terminal toxicity. Therefore, membrane toxicity could be manifested as membrane blocking and membrane expansion. The method established here may be useful for evaluating the interaction of toxins with membranes. PMID:17389047

Highly selective Ba2+ separations with acyclic, lipophilic di-[N-(X)sulfonyl carbamoyl] polyethers.

PubMed

Elshani, Sadik; Chun, Sangki; Amiri-Eliasi, Bijan; Bartsch, Richard A

2005-01-14

New lipophilic acyclic polyethers with two N-(X)sulfonyl carbamoyl groups of "tunable" acidity exhibit remarkable selectivity for Ba2+ over other alkaline earth metal ions in competitive solvent extraction and transport across polymer inclusion membranes.

Encapsulation of porphyrins and chlorins in biodegradable nanoparticles: the effect of dye lipophilicity on the extravasation and the photothrombic activity. A comparative study.

PubMed

Pegaz, Bernadette; Debefve, Elodie; Borle, Francois; Ballini, Jean-Pierre; van den Bergh, Hubert; Kouakou-Konan, Yvette Niamien

2005-07-01

In the present work, we performed a preclinical inter-comparison study using several photosensitizers with the goal of optimizing photodynamic therapy (PDT) for the treatment of choroidal neovascularization (CNV) associated with age-related macular degeneration. The tested molecules were the porphyrins meso-tetraphenylporphyrin (TPP) and meso-tetra-(4-carboxyphenyl)-porphyrin (TCPP), and the chlorins pheophorbide-a (Pheo-a) and chlorin e(6) (Ce(6)). Each of these molecules was entrapped in biodegradable nanoparticles (NP) based on poly(d,l-lactic acid). The influence of the degree of lipophilicity on the incorporation efficiency of the drug in the NPs, and on the dye leakage from blood vessels as well as on the photothrombic efficiency was investigated using the chick chorioallantoic membrane (CAM) as in vivo model. NP characterization showed that the dye was more effectively entrapped in the polymeric matrix when its degree of lipophilicity increased. While less lipophilic compounds (TCPP, Ce(6)) extravasate rather easily, the more lipophilic dyes (TPP, Pheo-a) tend to remain inside the blood vessels. After injection of a drug dose of 1 mg/kg body weight and a drug-light application interval of 1 min, irradiation with light doses ranging from 5 to 20 J/cm(2) led to the highest photothrombic efficiency when using the NPs loaded with the most lipophilic molecule (TPP). The latter induced vascular damage, which was significantly higher than that observed with the other molecules tested. Thus, in addition to minimal leakage from blood vessels, the TPP in NP formulation exhibited photothrombic efficiency similar to Visudyne which was also tested in the CAM model.

Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study.

PubMed

Haag, M D M; Hofman, A; Koudstaal, P J; Stricker, B H C; Breteler, M M B

2009-01-01

Cross-sectional reports suggest that statin users are less likely to have Alzheimer disease (AD). Prospective studies have provided inconsistent evidence. Moreover, it is unclear whether the association differs for lipophilic statins, those that could more easily pass the blood-brain barrier and hydrophilic statins. To prospectively evaluate whether use of statins is associated with the risk of AD, and to determine whether associations differ for lipophilic and hydrophilic statins. 6992 participants of the prospective, population-based Rotterdam Study were followed, from baseline (1990-1993) until January 2005 for incident AD. Data on all filled prescriptions came from pharmacy records. For each date on which each event occurred, cholesterol-lowering drug use for the person who experienced the event and all remaining persons in the cohort was categorised as "any" or "never" use. A distinction was made between statin, lipophilic and hydrophilic statins, and non-statin cholesterol-lowering drugs. Data were analysed with the Cox regression analysis, adjusting for sex, age and potential confounders. During follow-up (mean 9 years), 582 persons developed AD. Compared with never use of cholesterol-lowering drugs, statin use was associated with a decreased risk of AD (HR 0.57; 95% CI 0.37 to 0.90), but non-statin cholesterol-lowering drug use was not (HR 1.05; 95% CI 0.45 to 2.44). HRs were equal for lipophilic (HR 0.54; 95% CI 0.32 to 0.89) and hydrophilic statins (HR 0.54; 95% CI 0.26 to 1.11). In the general population, the use of statins, but not of non-statin cholesterol-lowering drugs, was associated with a lower risk of AD compared with never use of cholesterol-lowering drugs. The protective effect was independent of the lipophilicity of statins.

Extravascular transport of drugs in tumor tissue: effect of lipophilicity on diffusion of tirapazamine analogues in multicellular layer cultures.

PubMed

Pruijn, Frederik B; Sturman, Joanna R; Liyanage, H D Sarath; Hicks, Kevin O; Hay, Michael P; Wilson, William R

2005-02-24

The extravascular diffusion of antitumor agents is a key determinant of their therapeutic activity, but the relationships between physicochemical properties of drugs and their extravascular transport are poorly understood. It is well-known that drug lipophilicity plays an important role in transport across biological membranes, but the net effect of lipophilicity on transport through multiple layers of tumor cells is less clear. This study examines the influence of lipophilicity (measured as the octanol-water partition coefficient P) on the extravascular transport properties of the hypoxic cytotoxin tirapazamine (TPZ, 1) and a series of 13 neutral analogues, using multicellular layers (MCLs) of HT29 human colon carcinoma cells as an in vitro model for the extravascular compartment of tumors. Flux of drugs across MCLs was determined using diffusion chambers, with the concentration-time profile on both sides of the MCL measured by HPLC. Diffusion coefficients in the MCLs (D(MCL)) were inversely proportional to M(r)(0.5) (M(r), relative molecular weight), although this was a minor contributor to differences between compounds over the narrow M(r) range investigated. Differences in lipophilicity had a larger effect, with a sigmoidal dependence of D(MCL) on log P. Correcting for M(r) differences, lipophilic compounds (log P > 1.5) had ca. 15-fold higher D(MCL) than hydrophilic compounds (log P < -1). Using a pharmacokinetic/pharmacodynamic (PK/PD) model in which diffusion in the extravascular compartment of tumors is considered explicitly, we demonstrated that hypoxic cell kill is very sensitive to changes in extravascular diffusion coefficient of TPZ analogues within this range. This study shows that simple monosubstitution of TPZ can alter log P enough to markedly improve extravascular transport and activity against target cells, especially if rates of metabolic activation are also optimized.

Lipophilic phytochemicals from banana fruits of several Musa species.

PubMed

Vilela, Carla; Santos, Sónia A O; Villaverde, Juan J; Oliveira, Lúcia; Nunes, Alberto; Cordeiro, Nereida; Freire, Carmen S R; Silvestre, Armando J D

2014-11-01

The chemical composition of the lipophilic extract of ripe pulp of banana fruit from several banana cultivars belonging to the Musa acuminata and Musa balbisiana species (namely 'Chinese Cavendish', 'Giant Cavendish', 'Dwarf Red', 'Grand Nain', 'Eilon', 'Gruesa', 'Silver', 'Ricasa', 'Williams' and 'Zelig') was studied by gas chromatography-mass spectrometry for the first time. The banana cultivars showed similar amounts of lipophilic extractives (ca. 0.4% of dry material weight) as well as qualitative chemical compositions. The major groups of compounds identified in these fractions were fatty acids and sterols making up 68.6-84.3% and 11.1-28.0%, respectively, of the total amount of lipophilic components. Smaller amounts of long chain aliphatic alcohols and α-tocopherol were also identified. These results are a relevant contribution for the valorisation of these banana cultivars as sources of valuable phytochemicals (ω-3 and ω-6 fatty acids, and sterols) with well-established beneficial nutritional and health effects. Copyright © 2014 Elsevier Ltd. All rights reserved.

MLP Tools: a PyMOL plugin for using the molecular lipophilicity potential in computer-aided drug design

NASA Astrophysics Data System (ADS)

Oberhauser, Nils; Nurisso, Alessandra; Carrupt, Pierre-Alain

2014-05-01

The molecular lipophilicity potential (MLP) is a well-established method to calculate and visualize lipophilicity on molecules. We are here introducing a new computational tool named MLP Tools, written in the programming language Python, and conceived as a free plugin for the popular open source molecular viewer PyMOL. The plugin is divided into several sub-programs which allow the visualization of the MLP on molecular surfaces, as well as in three-dimensional space in order to analyze lipophilic properties of binding pockets. The sub-program Log MLP also implements the virtual log P which allows the prediction of the octanol/water partition coefficients on multiple three-dimensional conformations of the same molecule. An implementation on the recently introduced MLP GOLD procedure, improving the GOLD docking performance in hydrophobic pockets, is also part of the plugin. In this article, all functions of the MLP Tools will be described through a few chosen examples.

Unified model for the corneal permeability of related and diverse compounds with respect to their physicochemical properties.

PubMed

Yoshida, F; Topliss, J G

1996-08-01

Corneal permeability data taken from the literature were analyzed for possible quantitative relationships with physicochemical properties. Although a parabolic relationship was obtained with good correlation between lipophilicity, as expressed by the 1-octanol-water partition coefficients, log Poctanol (or the distribution coefficients, log D for ionizable compounds), and the permeability in individual analyses of compound classes such as beta-adrenoceptor blockers and steroids, the correlation was reduced when taken together. However, delta log P (i.e., log Poctanol-log Palkane) correlated inversely with the combined permeability data for beta-blockers and steroids and played a key role as a unifying variable. To a lesser extent, lipophilicity itself also contributes positively to corneal permeation. Even with the addition of miscellaneous compounds such as methanol and ibuprofen, the delta log P and lipophilicity terms were still significant. However, small molecules were likely to be underestimated, which is consistent with penetration via another pathway besides that governed by delta log P and lipophilicity.

Influence of finishing systems on hydrophilic and lipophilic oxygen radical absorbance capacity (ORAC) in beef.

PubMed

Wu, C; Duckett, S K; Neel, J P S; Fontenot, J P; Clapham, W M

2008-11-01

The aim of this research was to: (1) develop a reliable extraction procedure and assay to determine antioxidant activity in meat products, and (2) assess the effect of beef finishing system (forage-finished: alfalfa, pearl millet or mixed pastures vs. concentrate-finished) on longissimus muscle antioxidant activity. The effect of extraction method (ethanol concentration and extraction time), protein removal, and sample preparation method (pulverization or freeze drying) were first evaluated to develop an antioxidant assay for meat products. Beef extracts prepared with low ethanol concentrations (20%) demonstrated higher hydrophilic ORAC. Protein removal prior to extraction reduced hydrophilic ORAC values. Sample preparation method influenced both hydrophilic and lipophilic ORAC, with pulverized samples containing higher hydrophilic and lipophilic ORAC values. Beef cattle finishing system (Forage: alfalfa, pearl millet, or natural pasture vs. concentrates) had little impact on muscle hydrophilic ORAC, but muscle from forage finished beef contained greater lipophilic ORAC. In addition, broiling of steaks reduced hydrophilic ORAC.

Effect of drug lipophilicity on in vitro release rate from oil vehicles using nicotinic acid esters as model prodrug derivatives.

PubMed

Weng Larsen, S; Engelbrecht Thomsen, A E; Rinvar, E; Friis, G J; Larsen, C

2001-03-23

The rate constants for transfer of a homologous series of nicotinic acid esters from oil vehicles to aqueous buffer phases were determined using a rotating dialysis cell. The chemical stability of butyl nicotinate has been investigated at 60 degrees C over pH range 0.5--10. Maximum stability occurs at pH 4--5 and an inflection point was seen around the pK(a). For the nicotinic acid esters, a linear correlation was established between the first-order rate constant related to attainment of equilibrium, k(obs) and the apparent partition coefficient, P(app): log k(obs)=-0.83log P(app)+0.26 (k(obs) in h(-1), n=9). For hexyl nicotinate with a true partition coefficient of 4 it was possible to determine k(obs) by decreasing pH in the aqueous release medium to 2.05. Thus, under the latter experimental conditions estimation of the relative release rates for the esters were performed. The ratio between the specific rate constant k(ow), related to the transport from oil vehicle to aqueous phase, for ethyl and hexyl nicotinate was 139. The hydrophobic substituent constant for a methylene group, pi(CH(2)), was determined for nicotinic acid esters in different oil/buffer partitioning systems to 0.54--0.58. Addition of hydroxypropyl-beta-cyclodextrin to the aqueous release medium did not enhance the transport rate of the esters from the oil phase.

Lipophilicity of potent porphyrin-based antioxidants. Comparison of ortho and meta isomers of Mn(III) N-alkylpyridylporphyrins

PubMed Central

Kos, Ivan; Rebouças, Júlio S.; DeFreitas-Silva, Gilson; Salvemini, Daniela; Vujaskovic, Zeljko; Dewhirst, Mark W.; Spasojevic, Ivan; Batinic-Haberle, Ines

2009-01-01

Mn(III) N-alkylpyridylporphyrins are among the most potent known SOD mimics and catalytic peroxynitrite scavengers, and modulators of redox-based cellular transcriptional activity. In addition to their intrinsic antioxidant capacity, bioavailability plays major role in their in vivo efficacy. While of identical antioxidant capacity, lipophilic MnTnHex-2-PyP is up to 120-fold more efficient in reducing oxidative stress injuries than hydrophilic MnTE-2-PyP. Due to limitations of analytical nature, porphyrin lipophilicity has been often estimated by thin-layer chromatographic Rf parameter, instead of the standard n-octanol/water partition coefficient, POW. Herein we used a new methodological approach to finally describe the MnP lipophilicity, by the conventional log POW means, for a series of biologically active ortho and meta isomers of Mn(III) N-alkylpyridylporphyrins. Three new porphyrins (MnTnBu-3-PyP, MnTnHex-3-PyP and MnTnHep-2-PyP) were synthesized to strengthen the conclusions. The log POW was linearly related to Rf and to the number of carbons in the alkyl chain (nC) for both isomer series; the meta isomers being 10-fold more lipophilic than the analogous ortho porphyrins. Increasing the length of the alkyl chain for 1 carbon atom increases the log POW value ~ 1 log unit with both isomers. Dramatic ~4 and ~5 orders of magnitude increase in lipophilicity of ortho isomers by extending pyridyl alkyl chains from 2 (MnTE-2-PyP, log POW = −6.25) to 6 (MnTnHex-2-PyP, log POW = −2.29) and 8 carbon atoms (MnTnOct-2-PyP, log POW = −0.77) parallels the increased efficacy in several oxidative-stress injury models, particularly those of the central nervous system where transport across the blood-brain barrier is critical. Although meta isomers are only slightly less potent SOD mimics and antioxidants than their ortho analogues, their higher lipophilicity and smaller bulkiness may lead to a higher cellular uptake and overall similar effectiveness in vivo. PMID:19361553

Observations in simultaneous microencapsulation of 5-fluorouracil and leucovorin for combined pH-dependent release.

PubMed

Lamprecht, Alf; Yamamoto, Hiromitsu; Takeuchi, Hirofumi; Kawashima, Yoshiaki

2005-02-01

5-Fluorouracil (5-FU) in combination with leucovorin (LV) is nowadays the standard treatment in colon cancer and would be a candidate to be delivered orally to the colon. Eudragit P-4135F or Eudragit RS100 were used separately to prepare microspheres by an oil/oil emulsification process trapping 5-FU and LV simultaneously. Scanning electron microscopy permitted a structural analysis, process parameters were analyzed and drug loading and release profiles were recorded. Particle size varied between 123 (RS100) and 146 microm (P-4135F). Generally, higher encapsulation rates were found with RS100 (5-FU, 60.3+/-9.7%; LV, 81.4+/-8.6%) compared to P-4135F (5-FU, 48.3+/-2.0%; LV, 55.4+/-2.7%). Microparticles made from Eudragit RS100 released the incorporated drug combination within 8 h not exhibiting general differences between the kinetics of both drugs. P-4135F was found to maintain the undesired 5-FU release at pH 6.8 lower than 25% within 4 h while at pH 7.4, a nearly immediate release (within 15 min) was observed. Although the release was similar at pH 7.4, at pH 6.8 LV showed a distinct initial drug loss of about 60% and a complete release within 2 h. SEM analyses revealed a substantial presence of LV crystals on the particle surface provoking a distinct burst effect of LV. These observations were concluded to be related to the high lipophilicity of P-4135F provoking a separation between P-4135F and LV during the preparation process.

Semisynthesis, Cytotoxic Activity, and Oral Availability of New Lipophilic 9-Substituted Camptothecin Derivatives

PubMed Central

2013-01-01

Despite that 9-substituted camptothecins are promising candidates in cancer therapy, the limited accessibility to this position has reduced the studies of these derivatives to a few standard modifications. We report herein a novel semisynthetic route based on the Tscherniac–Einhorn reaction to synthesize new lipophilic camptothecin derivatives with amidomethyl and imidomethyl substitutions in position 9. Compounds were evaluated for their antiproliferative activity, topoisomerase I inhibition, and oral availability. Preliminary data demonstrated that bulky imidomethyl modification is an appropriate lipophilic substitution for an effective oral administration relative to topotecan. In addition, this general procedure paves the way for obtaining new camptothecin derivatives. PMID:24900725

Hydrophile-lipophile balance of alkyl ethoxylated surfactants as a function of intermolecular energies.

PubMed

Urbina-Villalba, G; Rogel, E; Márquez, M L; Reif, I

1994-06-01

The semiempirical MNDO method has been used in order to examine the variation of the molecular properties of hydrocarbons CnH2n + 2 (with 1 < or = n < or = 19) and ethylene oxide chains CH3(CH2CH2O)mCH3 (with 1 < or = m < or = 19) as a function of their molecular length. Least-square fits of those properties have been calculated, along with two mathematical relations between the hydrophile-lipophile balance of alkyl-phenol ethoxylated surfactants and (1) the ratio of molecular lengths between their lipophilic and hydrophilic branches; (2) the intermolecular energies between the molecules of surfactant, water and hexane.

Imaging Neuroinflammation in Post Traumatic Stress Disorder

DTIC Science & Technology

2012-11-01

Metabolite B = 0-30%), without evidence of lipophilic metabolites which can confound the analysis. 8 Figure 2 Left graph : Mean PSTD... graph : There is similar plasma protein binding of 18-F PBR111 in healthy and PTSD participants. Individual subject are data are indicated on the... graph . TSPO Binder status Both mixed and high afffinity TSPO binders were evident in the PTSD (4 high affinity binders, 4 mixed affinity

Lipophilic metabolite profiling of maize and sorghum seeds and seedlings, and their pest spotted stem borer larvae: a standardized GC-MS based approach.

PubMed

Kumar, Sandeep; Dhillon, Mukesh K

2015-03-01

In order to better understand the biochemical interactions and to identify new biomarkers for plant resistance against insects, we proposed a suitable lipophilic profiling method for insects and their host plants. The critical components of GC-MS based analysis are: sample amount, extraction, derivatization, temperature gradient, run time, and identification of peaks. For lipophilic metabolite profiling of maize and sorghum, and their insect pest, spotted stem borer larvae, we recommend 100 mg sample weight for seeds and insect samples (whole insect body), and 200 mg for seedlings. Maize and sorghum seeds required less time for fat extraction in comparison to their seedlings and the pest fed on these seedlings. GC-MS was standardized for better separation and intensity of peaks using different temperature gradients in the range of 180-300 C. A total of 48 lipophilic compounds encompassing various classes based on their functional groups such as fatty acids, fatty alcohols, hydrocarbons, sterols and terpenoids, vitamin derivative, etc. were separated in the seedlings (30), seeds (14), and the pest (26) in the retention time range of 3.22 to 29.41 min. This method could be useful to study nutritional aspects of different field crops in relation to various stresses apart from the analysis of lipophilic compounds for better understanding of insect-plant interactions.

Synthetic lipophilic antioxidant BO-653 suppresses HCV replication.

PubMed

Yasui, Fumihiko; Sudoh, Masayuki; Arai, Masaaki; Kohara, Michinori

2013-02-01

The influence of the intracellular redox state on the hepatitis C virus (HCV) life cycle is poorly understood. This study demonstrated the anti-HCV activity of 2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran (BO-653), a synthetic lipophilic antioxidant, and examined whether BO-653's antioxidant activity is integral to its anti-HCV activity. The anti-HCV activity of BO-653 was investigated in HuH-7 cells bearing an HCV subgenomic replicon (FLR3-1 cells) and in HuH-7 cells infected persistently with HCV (RMT-tri cells). BO-653 inhibition of HCV replication was also compared with that of several hydrophilic and lipophilic antioxidants. BO-653 suppressed HCV replication in FLR3-1 and RMT-tri cells in a concentration-dependent manner. The lipophilic antioxidants had stronger anti-HCV activities than the hydrophilic antioxidants, and BO-653 displayed the strongest anti-HCV activity of all the antioxidants examined. Therefore, the anti-HCV activity of BO-653 was examined in chimeric mice harboring human hepatocytes infected with HCV. The combination treatment of BO-653 and polyethylene glycol-conjugated interferon-α (PEG-IFN) decreased serum HCV RNA titer more than that seen with PEG-IFN alone. These findings suggest that both the lipophilic property and the antioxidant activity of BO-653 play an important role in the inhibition of HCV replication. Copyright © 2012 Wiley Periodicals, Inc.

Prediction of Log "P": ALOGPS Application in Medicinal Chemistry Education

ERIC Educational Resources Information Center

Kujawski, Jacek; Bernard, Marek K.; Janusz, Anna; Kuzma, Weronika

2012-01-01

Molecular hydrophobicity (lipophilicity), usually quantified as log "P" where "P" is the partition coefficient, is an important molecular characteristic in medicinal chemistry and drug design. The log "P" coefficient is one of the principal parameters for the estimation of lipophilicity of chemical compounds and pharmacokinetic properties. The…

Photoinduced Electron Transfer of PAMAM Dendrimer-Zinc(II) Porphyrin Associates at Polarized Liquid|Liquid Interfaces.

PubMed

Nagatani, Hirohisa; Sakae, Hiroki; Torikai, Taishi; Sagara, Takamasa; Imura, Hisanori

2015-06-09

The heterogeneous photoinduced electron-transfer reaction of the ion associates between NH2-terminated polyamidoamine (PAMAM) dendrimers and 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato zinc(II) (ZnTPPS(4-)) was studied at the polarized water|1,2-dichloroethane (DCE) interface. The positive photocurrent arising from the photoreduction of ZnTPPS(4-) by a lipophilic quencher, decamethylferrocene, in the interfacial region was significantly enhanced by the ion association with the PAMAM dendrimers. The photocurrent response of the dendrimer-ZnTPPS(4-) associates was dependent on the pH condition and on the generation of dendrimer. A few cationic additives such as polyallylamine and n-octyltrimethyammonium were also examined as alternatives to the PAMAM dendrimer, but the magnitude of the photocurrent enhancement was rather small. The high photoreactivity of the dendrimer-ZnTPPS(4-) associates was interpreted mainly as a result of the high interfacial concentration of photoreactive porphyrin units associated stably with the dendrimer which was preferably adsorbed at the polarized water|DCE interface. The photochemical data observed in the second and fourth generation PAMAM dendrimer systems demonstrated that the higher generation dendrimer which can incorporate a porphyrin molecule more completely in the interior is less efficient for the photocurrent enhancement at the interface. These results indicated that the photoreactivity of ionic reactant at a polarized liquid|liquid interface can readily be modified via ion association with the charged dendrimer.

The physiological determinants of drug-induced lysosomal stress resistance

PubMed Central

Woldemichael, Tehetina; Rosania, Gus R.

2017-01-01

Many weakly basic, lipophilic drugs accumulate in lysosomes and exert complex, pleiotropic effects on organelle structure and function. Thus, modeling how perturbations of lysosomal physiology affect the maintenance of lysosomal ion homeostasis is necessary to elucidate the key factors which determine the toxicological effects of lysosomotropic agents, in a cell-type dependent manner. Accordingly, a physiologically-based mathematical modeling and simulation approach was used to explore the dynamic, multi-parameter phenomenon of lysosomal stress. With this approach, parameters that are either directly involved in lysosomal ion transportation or lysosomal morphology were transiently altered to investigate their downstream effects on lysosomal physiology reflected by the changes they induce in lysosomal pH, chloride, and membrane potential. In addition, combinations of parameters were simultaneously altered to assess which parameter was most critical for recovery of normal lysosomal physiology. Lastly, to explore the relationship between organelle morphology and induced stress, we investigated the effects of parameters controlling organelle geometry on the restoration of normal lysosomal physiology following a transient perturbation. Collectively, our results indicate a key, interdependent role of V-ATPase number and membrane proton permeability in lysosomal stress tolerance. This suggests that the cell-type dependent regulation of V-ATPase subunit expression and turnover, together with the proton permeability properties of the lysosomal membrane, is critical to understand the differential sensitivity or resistance of different cell types to the toxic effects of lysosomotropic drugs. PMID:29117253

New icing media for quality enhancement of chilled hake (Merluccius merluccius) using a jumbo squid (Dosidicus gigas) skin extract.

PubMed

Ezquerra-Brauer, Josafat Marina; Miranda, José M; Chan-Higuera, Jesús Enrique; Barros-Velázquez, Jorge; Aubourg, Santiago P

2017-08-01

An advanced strategy for chilled fish preservation, based on the inclusion in ice of an extract of jumbo squid (Dosidicus gigas) skin (JSS), is proposed. Aqueous solutions including acetic acid-ethanol extracts of JSS were tested at two different concentrations as icing media, with the effects on the quality evolution of chilled hake (Merluccius merluccius) being monitored. A significant inhibition (P < 0.05) of microbial activity (aerobes, psychrotrophs, Enterobacteriaceae, proteolytic bacteria; pH, trimethylamine) was obtained in hake corresponding to the icing batch including the highest JSS concentration. Additionally, fish specimens from such icing conditions showed an inhibitory effect (P < 0.05) on lipid hydrolysis development, while no effect (P > 0.05) was depicted for lipid oxidation. Sensory analysis (skin and mucus development; eyes; gills; texture; external odour; raw and cooked flesh odour; flesh taste) indicated a shelf life extension of chilled hake stored in ice including the highest JSS concentration. A profitable use of JSS, an industrial by-product during jumbo squid commercialisation, has been developed in the present work, which leads to a remarkable microbial inhibition and a significant shelf life extension of chilled hake. In agreement with previous research, ommochrome pigments (i.e. lipophilic-type compounds) would be considered responsible for this preservative effect. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Complete factorial design to adjust pH and sugar concentrations in the inoculum phase of Ralstonia solanacearum to optimize P(3HB) production

PubMed Central

Alves, Mariane Igansi; Rodrigues, Amanda Ávila; Furlan, Lígia; da Silva Rodrigues, Rosane; Diaz de Oliveira, Patrícia; Vendruscolo, Claire Tondo; da Silveira Moreira, Angelita

2017-01-01

Poly(3-hydroxybutyrate) (P(3HB)) is a biodegradable plastic biopolymer that accumulates as lipophilic inclusions in the cytoplasm of some microorganisms. The biotechnological process by which P(3HB) is synthesized occurs in two phases. The first phase involves cell growth in a complex culture medium, while the second phase involves polymer accumulation in the presence of excess carbon sources. As such, the efficiency of the second phase depends on the first phase. The aim of this study was to evaluate culture media with different concentrations of sucrose and glucose and different pH values in the inoculum phase of Ralstonia solanacearum RS with the intention of identifying methods by which the biomass yield could be increased, subsequently enhancing the yield of P(3HB). The culture medium was formulated according to the experimental planning type of central composite rotational design 22. The independent variables were pH and sugar concentration (sucrose and glucose), and the dependent variables were OD600nm, dry cell weight (DCW), and P(3HB) yield. The highest cell growth, estimated by the OD600nm (20.6) and DCW (5.35) values, was obtained when sucrose was used in the culture medium at a concentration above 35 g.L-1 in combination with an acidic pH. High polymer (45%) accumulation was also achieved under these conditions. Using glucose, the best results for OD600nm (12.5) and DCW (2.74) were also obtained at acidic pH but with a sugar concentration at the minimum values evaluated. Due to the significant accumulation of polymer in the cells that were still in the growth phase, the accumulating microorganism P(3HB) Ralstonia solanacearum RS can be classified as having type II metabolism in relation to the polymer accumulation phase, which is different from other Ralstonia spp. studied until this time. PMID:28704411

Effect of lipophilicity of Mn (III) ortho N-alkylpyridyl- and diortho N, N'-diethylimidazolylporphyrins in two in-vitro models of oxygen and glucose deprivation-induced neuronal death.

PubMed

Wise-Faberowski, Lisa; Warner, David S; Spasojevic, Ivan; Batinic-Haberle, Ines

2009-04-01

In vivo investigations have confirmed the beneficial effects of hydrophilic, cationic Mn(III) porphyrin-based catalytic antioxidants in different models of oxidative stress. Using a cell culture model of rat mixed neuronal/glial cells, this study investigated the effect of MnTnOct-2-PyP5+ on oxygen and glucose deprivation (OGD)-induced cell death as compared to the effects of widely studied hydrophilic analogues MnTE-2-PyP5+ and MnTDE-2-ImP5+ and a standard compound, dizocilpine (MK-801). It was hypothesized that the octylpyridylporphyrin, MnTnOct-2-PyP5+, a lipophilic but equally potent antioxidant as the other two porphyrins, would be more efficacious in reducing OGD-induced cell death due to its higher bioavailability. Cell death was evaluated at 24 h using lactate dehydrogenase (LDH) release and propidium iodide staining. At concentrations from 3-100 microM, all three porphyrins reduced cell death as compared to cultures exposed to OGD alone, the effects depending upon the concentrations and type of treatment. To assess the effect of lipophilicity the additional experiments were performed using submicromolar concentrations of MnTnOct-2-PyP5+ in an organotypic hippocampal slice model of OGD with propidium iodide and Sytox staining. When compared to oxygen and glucose deprivation alone, concentrations of MnTnOct-2-PyP5+ as low as 0.01 microM significantly (p<0.001; power 1.0) reduced neuronal cells similar to control. This is the first in vitro study on the mammalian cells which indicates that MnTnOct-2-PyP5+ is up to 3000-fold more efficacious than equally potent hydrophilic analogues, due entirely to its increased bioavailability. Such remarkable increase in efficacy parallels 5.7-orders of magnitude increase in lipophilicity of MnTnOct-2-PyP5+ (log P=-0.77) when compared to MnTE-2-PyP5+ (log POW=-6.43), POW being partition coefficient between n-octanol and water.

Transferability and within- and between-laboratory reproducibilities of EpiSensA for predicting skin sensitization potential in vitro: A ring study in three laboratories.

PubMed

Mizumachi, Hideyuki; Sakuma, Megumi; Ikezumi, Mayu; Saito, Kazutoshi; Takeyoshi, Midori; Imai, Noriyasu; Okutomi, Hiroko; Umetsu, Asami; Motohashi, Hiroko; Watanabe, Mika; Miyazawa, Masaaki

2018-05-03

The epidermal sensitization assay (EpiSensA) is an in vitro skin sensitization test method based on gene expression of four markers related to the induction of skin sensitization; the assay uses commercially available reconstructed human epidermis. EpiSensA has exhibited an accuracy of 90% for 72 chemicals, including lipophilic chemicals and pre-/pro-haptens, when compared with the results of the murine local lymph node assay. In this work, a ring study was performed by one lead and two naive laboratories to evaluate the transferability, as well as within- and between-laboratory reproducibilities, of EpiSensA. Three non-coded chemicals (two lipophilic sensitizers and one non-sensitizer) were tested for the assessment of transferability and 10 coded chemicals (seven sensitizers and three non-sensitizers, including four lipophilic chemicals) were tested for the assessment of reproducibility. In the transferability phase, the non-coded chemicals (two sensitizers and one non-sensitizer) were correctly classified at the two naive laboratories, indicating that the EpiSensA protocol was transferred successfully. For the within-laboratory reproducibility, the data generated with three coded chemicals tested in three independent experiments in each laboratory gave consistent predictions within laboratories. For the between-laboratory reproducibility, 9 of the 10 coded chemicals tested once in each laboratory provided consistent predictions among the three laboratories. These results suggested that EpiSensA has good transferability, as well as within- and between-laboratory reproducibility. Copyright © 2018 John Wiley & Sons, Ltd.

Evaluation of ecotoxicological effects of benzophenone UV filters: Luminescent bacteria toxicity, genotoxicity and hormonal activity.

PubMed

Zhang, Qiuya; Ma, Xiaoyan; Dzakpasu, Mawuli; Wang, Xiaochang C

2017-08-01

The widespread use of organic ultraviolet (UV) filters in personal care products raises concerns about their potentially hazardous effects on human and ecosystem health. In this study, the toxicities of four commonly used benzophenones (BPs) UV filters including benzophenone (BP), 2-Hydroxybenzophenone (2HB), 2-Hydroxy-4-methoxybenzophenone (BP3), and 2-Hydroxy-4-methoxybenzophenone-5-sulfonicacid (BP4) in water were assayed in vitro using Vibrio fischeri, SOS/umu assay, and yeast estrogen screen (YES) assay, as well as in vivo using zebrafish larvae. The results showed that the luminescent bacteria toxicity, expressed as logEC 50 , increased with the lipophilicity (logKow) of BPs UV filters. Especially, since 2HB, BP3 and BP4 had different substituent groups, namely -OH, -OCH 3 and -SO 3 H, respectively, these substituent functional groups had a major contribution to the lipophilicity and acute toxicity of these BPs. Similar tendency was observed for the genotoxicity, expressed as the value of induction ratio=1.5. Moreover, all the target BPs UV filters showed estrogenic activity, but no significant influences of lipophilicity on the estrogenicity were observed, with BP3 having the weakest estrogenic efficiency in vitro. Although BP3 displayed no noticeable adverse effects in any in vitro assays, multiple hormonal activities were observed in zebrafish larvae including estrogenicity, anti-estrogenicity and anti-androgenicity by regulating the expression of target genes. The results indicated potential hazardous effects of BPs UV filters and the importance of the combination of toxicological evaluation methods including in vitro and in vivo assays. Copyright © 2017 Elsevier Inc. All rights reserved.

Enantio-selective optode for the β-blocker propranolol

NASA Astrophysics Data System (ADS)

He, Huarui; Uray, Georg; Wolfbeis, Otto S.

1991-03-01

We present a scheme for sensing optical isomers (enantiomers) of biogenic amines such as the Bblocker propranolol. Recognition of one of the enantiomers of propranolol is accomplished by specific interaction of the amine (which is present in the protonated ammonium form at physiological pH) with an optically active substrate (dibutyl tartrate) in a pvc membrane. As the ammonium ion is carried into the pvc membrane a proton is simultaneously released from the proton carrier (a lipophilic phenolic xanthene dye which undergoes protolytic dissociation in the pvc membrane) which thereby suffers a color change. The sensor responds to propranolol but also to other biogenic amines such as 1-phenylethylamine and norephedrine in the 20 pM to 10 mM range but has a pH-dependent response. The selectivity factors depend on the type of receptor and range from 0. 0 to 0. 30.

Solid lipid microparticles containing loratadine prepared using a Micromixer.

PubMed

Milak, Spomenka; Medlicott, Natalie; Tucker, Ian G

2006-12-01

Solid lipid microparticles were investigated as a taste-masking approach for a lipophilic weak base in a suspension. The idea was that the drug concentration in the aqueous phase of a suspension might be reduced by its partitioning into the solid lipid particles. Loratadine, as a model drug, was used to prepare Precirol ATO 5 microparticles by a Micromixer. The effects of three process variables: drug loading, PVA concentration and water/lipid ratio on the microparticle size, encapsulation efficiency, surface appearance, in-vitro release and drug partitioning in a suspension were studied. Loratadine release was slow in simulated saliva and very fast at the pH of stomach. In suspension of loratadine lipid microparticles, drug was released into the aqueous phase to the same concentration as in a drug suspension. Therefore, the usefulness of these microparticles for taste-masking in liquids is limited. However, they might be useful for taste-masking in solid dosage forms.

Bioconcentration of lipophilic compounds by some aquatic organisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hawker, D.W.; Connell, D.W.

1986-04-01

With nondegradable, lipophilic compounds having log P values ranging from 2 to 6, direct linear relationships have been found between the logarithms of the equilibrium bioconcentration factors, and also reciprocal clearance rate constants, with log P for daphnids and molluscs. These relationships permit calculation of the times required for equilibrium and significant bioconcentration of lipophilic chemicals. Compared with fish, these time periods are successively shorter for molluscs, then daphnids. The equilibrium biotic concentration was found to decrease with increasing chemical hydrophobicity for both molluscs and daphnids. Also, new linear relationships between the logarithm of the bioconcentration factor and log Pmore » were found for compounds not attaining equilibrium within finite exposure times.« less

2-Oxoamide inhibitors of cytosolic group IVA phospholipase A2 with reduced lipophilicity.

PubMed

Antonopoulou, Georgia; Magrioti, Victoria; Kokotou, Maroula G; Nikolaou, Aikaterini; Barbayianni, Efrosini; Mouchlis, Varnavas D; Dennis, Edward A; Kokotos, George

2016-10-01

Cytosolic GIVA phospholipase A2 (GIVA cPLA2) initiates the eicosanoid pathway of inflammation and thus inhibitors of this enzyme constitute novel potential agents for the treatment of inflammatory diseases. Traditionally, GIVA cPLA2 inhibitors have suffered systemically from high lipophilicity. We have developed a variety of long chain 2-oxoamides as inhibitors of GIVA PLA2. Among them, AX048 was found to produce a potent analgesic effect. We have now reduced the lipophilicity of AX048 by replacing the long aliphatic chain with a chain containing an ether linked aromatic ring with in vitro inhibitory activities similar to AX048. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lipophilization and MS characterization of the main anthocyanins purified from hibiscus flowers.

PubMed

Grajeda-Iglesias, Claudia; Salas, Erika; Barouh, Nathalie; Baréa, Bruno; Figueroa-Espinoza, Maria Cruz

2017-09-01

Hibiscus sabdariffa flowers represent an interesting source of anthocyanins, one of the most important plant pigments, which are responsible of the intense red color of the calyces, and have potential as natural colorants for food applications. Nevertheless, anthocyanins are highly hydrosoluble and unstable compounds. On this basis, the aim of this work was to increase the lipophilicity of the hibiscus anthocyanins by lipophilization, in order to obtain amphiphilic colorants, which could be easily incorporated in lipid-rich food matrices. Octanoyl derivatives of delphinidin-3-O-sambubioside and cyanidin-3-O-sambubioside were chemically obtained for the first time, and characterized by means of HPLC-ESI-MS data. Copyright © 2017. Published by Elsevier Ltd.

Tetrapeptide Inhibitors of the Glutamate Vesicular Transporter (VGLUT)

PubMed Central

Patel, Sarjubhai A.; Nagy, Jon O.; Bolstad, Erin D.; Gerdes, John M.; Thompson, Charles M.

2007-01-01

Quinoline-2,4-dicaboxylic acids (QDCs) bearing lipophilic substituents in the 6- or 7-position were shown to be inhibitors of the glutamate vesicular transporter (VGLUT). Using the arrangement of the QDC lipophilic substituents as a template, libraries of X1X2EF and X1X2EW tetrapeptides were synthesized and tested as VGLUT inhibitors. The peptides QIEW and WNEF were found to be the most potent. Further stereochemical deconvolution of these two peptides showed dQlIdElW to be the best inhibitor (Ki = 828 ± 252 μM). Modeling and overlay of the tetrapeptide inhibitors with the existing pharmacophore showed that H-bonding and lipophilic residues are important for VGLUT binding. PMID:17662605

An extended model based on the modified Nernst-Planck equation for describing transdermal iontophoresis of weak electrolytes.

PubMed

Imanidis, Georgios; Luetolf, Peter

2006-07-01

An extended model for iontophoretic enhancement of transdermal drug permeation under constant voltage is described based on the previously modified Nernst-Planck equation, which included the effect of convective solvent flow. This model resulted in an analytical expression for the enhancement factor as a function of applied voltage, convective flow velocity due to electroosmosis, ratio of lipid to aqueous pathway passive permeability, and weighted average net ionic valence of the permeant in the aqueous epidermis domain. The shift of pH in the epidermis compared to bulk caused by the electrical double layer at the lipid-aqueous domain interface was evaluated using the Poisson-Boltzmann equation. This was solved numerically for representative surface charge densities and yielded pH differences between bulk and epidermal aqueous domain between 0.05 and 0.4 pH units. The developed model was used to analyze the experimental enhancement of an amphoteric weak electrolyte measured in vitro using human cadaver epidermis and a voltage of 250 mV at different pH values. Parameter values characterizing the involved factors were determined that yielded the experimental enhancement factors and passive permeability coefficients at all pH values. The model provided a very good agreement between experimental and calculated enhancement and passive permeability. The deduced parameters showed (i) that the pH shift in the aqueous permeation pathway had a notable effect on the ionic valence and the partitioning of the drug in this domain for a high surface charge density and depending on the pK(a) and pI of the drug in relation to the bulk pH; (ii) the magnitude and the direction of convective transport due to electroosmosis typically reflected the density and sign, respectively, of surface charge of the tissue and its effect on enhancement was substantial for bulk pH values differing from the pI of epidermal tissue; (iii) the aqueous pathway predominantly determined passive permeability of the studied compound despite its measurable lipophilicity and therefore the lipid pathway did not notably affect enhancement. Hence, the proposed model can provide a good quantitative insight into the interplay between different phenomena and permeant properties influencing iontophoresis and can potentially be used as a predictive tool of the process.

Correlation of lipophilicity with mosquito larvicidal and repellent activities of novel trifluoromethylphenyl amides

USDA-ARS?s Scientific Manuscript database

For a chemical to have a biological impact on an organism, the molecules must be capable of being transported across the membranes of cells. Lipophilic insecticides that can pass through lipid bilayers and penetrate the insect cuticle can lead to rapid intoxication or mortality by acting on the nerv...

Assessing the lipophilicity of fragments and early hits

NASA Astrophysics Data System (ADS)

Mortenson, Paul N.; Murray, Christopher W.

2011-07-01

A key challenge in many drug discovery programs is to accurately assess the potential value of screening hits. This is particularly true in fragment-based drug design (FBDD), where the hits often bind relatively weakly, but are correspondingly small. Ligand efficiency (LE) considers both the potency and the size of the molecule, and enables us to estimate whether or not an initial hit is likely to be optimisable to a potent, druglike lead. While size is a key property that needs to be controlled in a small molecule drug, there are a number of additional properties that should also be considered. Lipophilicity is amongst the most important of these additional properties, and here we present a new efficiency index (LLEAT) that combines lipophilicity, size and potency. The index is intuitively defined, and has been designed to have the same target value and dynamic range as LE, making it easily interpretable by medicinal chemists. Monitoring both LE and LLEAT should help both in the selection of more promising fragment hits, and controlling molecular weight and lipophilicity during optimisation.

Profiling of lipophilic and phenolic phytochemicals of four cultivars from cherimoya (Annona cherimola Mill.).

PubMed

Santos, Sónia A O; Vilela, Carla; Camacho, João F; Cordeiro, Nereida; Gouveia, Manuela; Freire, Carmen S R; Silvestre, Armando J D

2016-11-15

The lipophilic and phenolic extractives of the ripe mesocarp of four cherimoya cultivars ('Perry Vidal', 'Mateus I', 'Mateus III' and 'Funchal') from Madeira Island, were studied for the first time. The predominant lipophilic compounds are kaurene diterpenes (42.2-59.6%), fatty acids (18.0-35.6%) and sterols (9.6-23.7%). Kaur-16-en-19-oic acid is the major lipophilic component of all cultivars accounting between 554 and 1350mgkg(-1) of dry material. The studied fruits also contain a high variety of flavan-3-ols, including galloylated and non-galloylated compounds. Five phenolic compounds were identified for the first time: catechin, (epi)catechin-(epi)gallocatechin, (epi)gallocatechin, (epi)afzelechin-(epi)catechin and procyanidin tetramer. 'Mateus I' and 'Mateus III' cultivars present the highest content of phenolic compounds (6299 and 9603mgkg(-1) of dry weight, respectively). These results support the use of this fruit as a rich source of health-promoting components, with the capacity to prevent or delay the progress of oxidative-stress related disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Plechanovová, Anna; Byun, Youngjoo; Alquicer, Glenda

2012-10-09

Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance ofmore » nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII.« less

Correlation of the lipophilicity of xenobiotics with their synergistic effects on DNA synthesis in human fibroblasts.

PubMed

Jacobi, H; Leier, G; Witte, I

1996-04-01

The binary combination effects of DNA synthesis of human fibroblasts were investigated using 2,4-D with 15 xenobiotics of different chemical substance classes. Results were compared with previous investigations on cell growth. Each of the 15 chemicals tested at their no effect concentrations (NOEC's) increased the effects of 2,4-D on DNA synthesis. Thereby, the EC20 value of 2,4-D was reduced by approximately 40% in the combinations. The NOEC's of the xenobiotics used in the combinations varied by a factor of 1,600 and depended strongly on the lipophilicity of the agents combined with 2,4-D. A significant statistical correlation of r = 0.90 was found between the NOEC's of the 15 combined xenobiotics and their lipophilicity. The combination effects on DNA synthesis were similar to those on cell growth. The regression lines of the relationship between the NOEC's and lipophilicity in both assays showed only slight differences in the slopes. This is an additional confirmation of our hypothesis on a facilitated uptake of 2,4-D in the binary combinations.

Combined microplate-ABTS and HPLC-ABTS analysis of tomato and pepper extracts reveals synergetic and antagonist effects of their lipophilic antioxidative components.

PubMed

Le Grandois, Julie; Guffond, Delphine; Hamon, Erwann; Marchioni, Eric; Werner, Dalal

2017-05-15

The antioxidant capacity of 9 pure lipophilic compounds was examined by microplate-ABTS and HPLC-ABTS, using similar experimental conditions. Results obtained showed that HPLC-ABTS method can be used for a rapid determination of individual antioxidant capacity of compounds in standard solutions or complex mixtures. The application of both methods to real lipophilic extracts from tomato (Solanum lycopersicum L.), green and red peppers (Capsicum annuum) reveals possible interactions between antioxidants. Thus, synthetic mixtures of two compounds identified in tomato and peppers were measured using microplate-ABTS and HPLC-ABTS. Synergistic effects were observed between (β-carotene-capsanthin) (1:9) and (1:1), (α-tocopherol-capsanthin) (1:9), (lutein-lycopene) (9:1) and (capsanthin-δ-tocopherol) (9:1). On the contrary, antagonistic effects were observed for (lutein-δ-tocopherol) and (α-tocopherol-δ-tocopherol). The interactions observed with two-compound mixtures are not systematically observed in the natural lipophilic extracts from tomato, green and red peppers, probably since extracts are more complex and are susceptible to cause interferences. Copyright © 2016 Elsevier Ltd. All rights reserved.

Insights on novel particulate self-assembled drug delivery beads based on partial inclusion complexes between triglycerides and cyclodextrins.

PubMed

Aburahma, Mona Hassan

2016-09-01

Most of the newly designed drug molecules are lipophilic in nature and often encounter erratic absorption and low bioavailability after oral administration. Finding ways to enhance the absorption and bioavailability of these lipophilic drugs is one of the major challenges that face pharmaceutical industry nowadays. In view of that, the purpose of this review is to shed some light on a novel particulate self-assembling system named "beads" than can act as a safe carrier for delivering lipophilic drugs. The beads are prepared simply by mixing oils with cyclodextrin (CD) aqueous solution in mild conditions. A unique interaction between oil components and CD molecules occurs to form in situ surface-active complexes which are prerequisites for beads formation. This review mainly focuses on the fundamentals of beads preparation through reviewing present, yet scarce, literature. The key methods used for beads characterization are discussed in details. Also, the potential mechanisms by which beads increase the bioavailability of lipophilic drugs are illustrated. Finally, the related research areas that needs to be addressed in future for optimizing this promising delivery system are briefly outlined.

Temperature Dependence of Nonelectrolyte Permeation across Red Cell Membranes

PubMed Central

Galey, W. R.; Owen, J. D.; Solomon, A. K.

1973-01-01

The temperature dependence of permeation across human red cell membranes has been determined for a series of hydrophilic and lipophilic solutes, including urea and two methyl substituted derivatives, all the straight-chain amides from formamide through valeramide and the two isomers, isobutyramide and isovaleramide. The temperature coefficient for permeation by all the hydrophilic solutes is 12 kcal mol-1 or less, whereas that for all the lipophilic solutes is 19 kcal mol-1 or greater. This difference is consonant with the view that hydrophilic molecules cross the membrane by a path different from that taken by the lipophilic ones. The thermodynamic parameters associated with lipophile permeation have been studied in detail. ΔG is negative for adsorption of lipophilic amides onto an oil-water interface, whereas it is positive for transfer of the polar head from the aqueous medium to bulk lipid solvent. Application of absolute reaction rate theory makes it possible to make a clear distinction between diffusion across the water-red cell membrane interface and diffusion within the membrane. Diffusion coefficients and apparent activation enthalpies and entropies have been computed for each process. Transfer of the polar head from the solvent into the interface is characterized by ΔG ‡ = 0 kcal mol-1 and ΔS ‡ negative, whereas both of these parameters have large positive values for diffusion within the membrane. Diffusion within the membrane is similar to what is expected for diffusion through a highly associated viscous fluid. PMID:4708405

Lipophilization of somatostatin analog RC-160 improves its bioactivity and stability.

PubMed

Dasgupta, P; Singh, A T; Mukherjee, R

1999-07-01

Acromegaly is a symptomatically disabling condition, resulting from a growth hormone (GH) secreting pituitary tumor. The somatostatin analog RC- 160 is known to potently inhibit hypersecretion of GH, from pituitary adenomas. However, the therapeutic potential of RC-160, is limited by its short serum half life. To overcome this limitation, fatty acids with carbon chain lengths ranging from 4 to 18 were conjugated to RC-160. The GH-inhibitory activity of these lipopeptides, as well as their binding profile to somatostatin receptors, on the rat pituitary adenoma cell line GH3 was studied in vitro. The relative stability of lipophilized RC-160 towards degradation by crude papaya protease was also determined. The long chain lipopeptides, like myristoyl-RC-160 (carbon chain length = 14) were found to exhibit greater receptor affinity and GH-inhibitory activity, as compared to their counterparts of lower chain lengths. However, the receptor affinity and GH-inhibitory activity of stearoyl-RC-160 (carbon chain length = 18), was found to lower than RC-160 and its lipophilized derivatives. Unlike RC-160, the myristoylated derivative was found to have significantly greater resistance to protease and serum degradation (p < 0.01). Lipophilization of RC-160 with long chain fatty acids improves its stability and GH-inhibitory activity. The activity of lipophilized RC-160 seems to increase with increasing hydrophobicity of the lipopeptide, and reaches a maxima at myristoyl-RC-160 for GH3. Hence, optimizing the hydrophobicity should be an important consideration governing the design and synthesis of bioactive lipopeptides.

Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives.

PubMed

Milosevic, Natasa P; Kojic, Vesna; Curcic, Jelena; Jakimov, Dimitar; Milic, Natasa; Banjac, Nebojsa; Uscumlic, Gordana; Kaliszan, Roman

2017-04-15

Design of a new drug entity is usually preceded by analysis of quantitative structure activity (properties) relationships, QSA(P)R. Six newly synthesized succinimide derivatives have been determined for (i) in silico physico-chemical descriptors, pharmacokinetic and toxicity predictors, (ii) in vitro biological activity on four different carcinoma cell lines and on normal fetal lung cells and (iii) lipophilicity on liquid chromatography. All compounds observed were predicted for good permeability and solubility, good oral absorption rate and moderate volume of distribution as well as for modest blood brain permeation, followed by acceptable observed toxicity. In silico determined lipophilicity, permeability through jejunum and aqueous solubility were correlated with experimentally obtained lipophilic constants (by use of high pressure liquid chromatography) and linear correlations were obtained. Absorption rate and volume of distribution were predicted by chromatographic lipophilicity measurements while permeation through blood bran barrier was predicted dominantly by molecular size defined with molecular weight. Five compounds have demonstrated antiproliferative activity toward cervix carcinoma HeLa cell lines; three were cytotoxic against breast carcinoma MCF-7 cells, while one inhibited proliferation of colon carcinoma HT-29 cell lines. Only one compound was cytotoxic toward normal cell lines, while other compounds were proven as safe. Antiproliferative potential against HeLa cells was described as exponential function of lipophilicity. Based on obtained results, lead compounds were selected. Copyright © 2017 Elsevier B.V. All rights reserved.

Improved Cytotoxic Effect of Doxorubicin by Its Combination with Sclareol in Solid Lipid Nanoparticle Suspension.

PubMed

Oliveira, Mariana Silva; Lima, Bruno Henrique Santiago; Goulart, Gisele Assis Castro; Mussi, Samuel Vidal; Borges, Gabriel Silva Marques; Oréfice, Rodrigo Lambert; Ferreira, Lucas Antônio Miranda

2018-08-01

This work aims to develop, characterize, and evaluate the anticancer activity of solid lipid nanoparticles (SLN) containing doxorubicin (DOX), an antitumoral from the antracycline class, and sclareol (SC), a lipophilic labdene diterpene (SLN-DOX-SC). The SLN were characterized by Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), Small Angle X-ray Diffraction (SAXS), in vitro release, transmission electron microscopy, and polarized light microscopy. Evaluation of cell viability was performed in two cell cultures: MCF-7 (human breast cancer) and 4T1 (murine breast cancer). The SLN showed a size in the range of 128 nm, negative zeta potential, DOX encapsulation efficiency (EE) of 99%, and drug loading (DL) of 66 mg/g. Characterization of the formulation by DSC, XRD, and SAXS revealed the presence of DOX inside the nanoparticles of SLN and suggested increased expulsion/release of this drug when associated with SC. The release profiles revealed that the SLN-DOX-SC showed controlled release of DOX at pH 7.4 with enhanced drug release at low pH, useful for cancer treatment. The SLN-DOX-SC demonstrated to be more effective than the free DOX against 4T1 cells. So, the developed SLN efficiently encapsulate DOX and SC and show good potential as an alternative for cancer treatment.

Ion-pair partition of quarternary ammonium drugs: the influence of counter ions of different lipophilicity, size, and flexibility.

PubMed

Takács-Novák, K; Szász, G

1999-10-01

The ion-pair partition of quaternary ammonium (QA) pharmacons with organic counter ions of different lipophilicity, size, shape and flexibility was studied to elucidate relationships between ion-pair formation and chemical structure. The apparent partition coefficient (P') of 4 QAs was measured in octanol/pH 7.4 phosphate buffer system by the shake-flask method as a function of molar excess of ten counter ions (Y), namely: mesylate (MES), acetate (AC), pyruvate (PYRU), nicotinate (NIC), hydrogenfumarate (HFUM), hydrogenmaleate (HMAL), p-toluenesulfonate (PTS), caproate (CPR), deoxycholate (DOC) and prostaglandin E1 anion (PGE1). Based on 118 of highly precise logP' values (SD< 0.05), the intrinsic lipophilicity (without external counter ions) and the ion-pair partition of QAs (with different counter ions) were characterized. Linear correlation was found between the logP' of ion-pairs and the size of the counter ions described by the solvent accessible surface area (SASA). The lipophilicity increasing effect of the counter ions were quantified and the following order was established: DOC approximate to PGE1 > CPR approximate to PTS > NIC approximate to HMAL > PYRU approximate to AC approximate to MES approximate to HFUM. Analyzing the lipophilicity/molar ratio (QA:Y) profile, the differences in the ion-pair formation were shown and attributed to the differences in the flexibility/rigidity and size both of QA and Y. Since the largest (in average, 300 X) lipophilicity enhancement was found by the influence of DOC and PGE1 and considerable (on average 40 X) increase was observed by CPR and PTS, it was concluded that bile acids and prostaglandin anions may play a significant role in the ion-pair transport of quaternary ammonium drugs and caproic acid and p-toluenesulfonic acid may be useful salt forming agents to improve the pharmacokinetics of hydrophilic drugs.

Formulation and in vitro release evaluation of newly synthesized palm kernel oil esters-based nanoemulsion delivery system for 30% ethanolic dried extract derived from local Phyllanthus urinaria for skin antiaging

PubMed Central

Mahdi, Elrashid Saleh; Noor, Azmin Mohd; Sakeena, Mohamed Hameem; Abdullah, Ghassan Z; Abdulkarim, Muthanna F; Sattar, Munavvar Abdul

2011-01-01

Background Recently there has been a remarkable surge of interest about natural products and their applications in the cosmetic industry. Topical delivery of antioxidants from natural sources is one of the approaches used to reverse signs of skin aging. The aim of this research was to develop a nanoemulsion cream for topical delivery of 30% ethanolic extract derived from local Phyllanthus urinaria (P. urinaria) for skin antiaging. Methods Palm kernel oil esters (PKOEs)-based nanoemulsions were loaded with P. urinaria extract using a spontaneous method and characterized with respect to particle size, zeta potential, and rheological properties. The release profile of the extract was evaluated using in vitro Franz diffusion cells from an artificial membrane and the antioxidant activity of the extract released was evaluated using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) method. Results Formulation F12 consisted of wt/wt, 0.05% P. urinaria extract, 1% cetyl alcohol, 0.5% glyceryl monostearate, 12% PKOEs, and 27% Tween® 80/Span® 80 (9/1) with a hydrophilic lipophilic balance of 13.9, and a 59.5% phosphate buffer system at pH 7.4. Formulation F36 was comprised of 0.05% P. urinaria extract, 1% cetyl alcohol, 1% glyceryl monostearate, 14% PKOEs, 28% Tween® 80/Span® 80 (9/1) with a hydrophilic lipophilic balance of 13.9, and 56% phosphate buffer system at pH 7.4 with shear thinning and thixotropy. The droplet size of F12 and F36 was 30.74 nm and 35.71 nm, respectively, and their nanosizes were confirmed by transmission electron microscopy images. Thereafter, 51.30% and 51.02% of the loaded extract was released from F12 and F36 through an artificial cellulose membrane, scavenging 29.89% and 30.05% of DPPH radical activity, respectively. Conclusion The P. urinaria extract was successfully incorporated into a PKOEs-based nanoemulsion delivery system. In vitro release of the extract from the formulations showed DPPH radical scavenging activity. These formulations can neutralize reactive oxygen species and counteract oxidative injury induced by ultraviolet radiation and thereby ameliorate skin aging. PMID:22072884

Readily prepared biodegradable nanoparticles to formulate poorly water soluble drugs improving their pharmacological properties: The example of trabectedin.

PubMed

Capasso Palmiero, Umberto; Morosi, Lavinia; Bello, Ezia; Ponzo, Marianna; Frapolli, Roberta; Matteo, Cristina; Ferrari, Mariella; Zucchetti, Massimo; Minoli, Lucia; De Maglie, Marcella; Romanelli, Pierpaolo; Morbidelli, Massimo; D'Incalci, Maurizio; Moscatelli, Davide

2018-04-28

The improvement of the pharmacological profile of lipophilic drug formulations is one of the main successes achieved using nanoparticles (NPs) in medicine. However, the complex synthesis procedure and numerous post-processing steps hamper the cost-effective use of these formulations. In this work, an approach which requires only a syringe to produce self-assembling biodegradable and biocompatible poly(caprolactone)-based NPs is developed. The effective synthesis of monodisperse NPs has been made possible by the optimization of the block-copolymer synthesized via a combination of ring opening polymerization and reversible addition-fragmentation chain transfer polymerization. These NPs can be used to formulate lipophilic drugs that are barely soluble in water, such as trabectedin, a potent anticancer therapeutic. Its biodistribution and antitumor activity have been compared with the commercially available formulation Yondelis®. The results indicate that this trabectedin NP formulation performs with the same antitumor activity as Yondelis®, but does not have the drawback of severe local vascular toxicity in the injection site. Copyright © 2018 Elsevier B.V. All rights reserved.

Statins as neuroprotectants: a comparative in vitro study of lipophilicity, blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death.

PubMed

Sierra, Saleta; Ramos, Maria C; Molina, Pilar; Esteo, Cynthia; Vázquez, Jose Antonio; Burgos, Javier S

2011-01-01

There is growing evidence to support the hypothesis that statins may act as neuroprotectants in several neuropathological conditions, including Alzheimer's disease. The mechanisms for neuroprotection are only partially understood, however, and pleiotropic phenomena could be involved. We have made a comparative study of 9 statins (lovastatin, mevastatin, pravastatin, simvastatin, cerivastatin, atorvastatin, fluvastatin, pitavastatin, and rosuvastatin), analyzing several parameters that could be related to neuroprotection, such as chemical structure, lipophilicity, potential blood-brain-barrier penetration (BBB), 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibition, cholesterol modulation in neurons, glia, and human hepatocyte cell lines, and protection against neurodegeneration caused by tau hyperphosphorylation induced by okadaic acid. Our results indicate that monacolin J derivatives (natural and semi-synthetic statins) are the best candidates for the prevention of neurodegenerative conditions due to their higher potential BBB penetration capacity, cholesterol lowering effect on neurons with a satisfactory safety profile, and in vitro protection against cell death caused by okadaic acid in culture. Among the nine statins studied, simvastatin presented the best characteristics for preventing neurodegenerative conditions.

[Studies on development of pharmaceutical preparation with the purpose of improving controlled-release and bioavailability].

PubMed

Goto, S

1995-11-01

During the past fifteen years, the experiments based on three main propositions were proceeded to carry out in our laboratory, that is, (1) Microencapsulation: The method of solvent evaporation in water or oily phases was adopted because of its comparative simplicity in the procedure and its high reproducibility. The application of pharmacokinetic consideration to in vivo evaluation of microencapsulated drugs using beagle dogs intended for obtaining controlled-release by oral administration. The pullulan acetate phthalate microcapsules containing cefadroxil were prepared by the solvent evaporation method in liquid paraffin and showed a zero-order dissolution pattern in pH 6-7.4. (2) Rectal gel preparation: The hydrogels and xerogels were prepared by Eudispert hv. These gels have excellent staying properties in the lower part of the rectum, over a fairly long period. Eudispert hv hydrogels or xerogels containing propentfylline were tested for avoidance of the first-pass metabolism. The absolute bioavailability of propentofylline from gel preparations was almost 100%. (3) Binary vehicle for transdermal delivery: The effects of glycerides, short-chain alcohols and their binary vehicles as donor components on the skin permeation of ketoprofen across the excised hairless mouse skin were evaluated with the diffusion cell. Among single vehicles, Panasate 800 as lipophilic vehicle and ethanol as hydrophilic vehicle showed the effective permeation flux of ketoprofen. The greatest enhancement was observed in an ethanol/Panasate 800 (40/60) binary vehicle. The relationship between lipophilicity and skin permeability of 16 drugs from the ethanol/Panasate 800 (40/60) binary vehicle showed a parabolic shape with a peak at a more hydrophilic range compared with other past references.

Electrochemical ion transfer mediated by a lipophilic Os(ii)/Os(iii) dinonyl bipyridyl probe incorporated in thin film membranes.

PubMed

Jansod, Sutida; Wang, Lu; Cuartero, Maria; Bakker, Eric

2017-09-28

A new lipophilic dinonyl bipyridyl Os(ii)/Os(iii) complex successfully mediates ion transfer processes across voltammetric thin membranes. An added lipophilic cation-exchanger may impose voltammetric anion or cation transfer waves of Gaussian shape that are reversible and repeatable. The peak potential is found to shift with the ion concentration in agreement with the Nernst equation. The addition of tridodecylmethylammonium nitrate to the polymeric film dramatically reduces the peak separation from 240 mV to 65 mV, and the peak width to a near-theoretical value of 85 mV, which agrees with a surface confined process. It is suggested that the cationic additive serves as a phase transfer catalyst.

Impact of Stereospecific Intramolecular Hydrogen Bonding on Cell Permeability and Physicochemical Properties

PubMed Central

2014-01-01

Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pKa, and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH→NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure–property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski’s rule of 5. PMID:24524242

Lipophilicity of some guaianolides isolated from two endemic subspecies of Amphoricarpos neumayeri (Asteraceae) from Montenegro.

PubMed

Atrrog, Abubaker A B; Natić, Maja; Tosti, Tomislav; Milojković-Opsenica, Dusanka; Dordević, Iris; Tesević, Vele; Jadranin, Milka; Milosavljević, Slobodan; Lazić, Milan; Radulović, Sinisa; Tesić, Zivoslav

2009-03-01

In this study 10 guaianolide-type sesquiterpene gamma-lactones named amphoricarpolides, isolated from the aerial parts of two endemic subspecies of Amphoricarpos neumayeri (ssp. neumayeri and ssp. murbeckii Bosnjak), were investigated by means of reversed-phase thin-layer chromatography. Methanol-water and tetrahydrofuran-water binary mixtures were used as mobile phase in order to determine lipophilicity parameters R (0) (M) and C(0). Some of the investigated compounds were screened for their cytotoxic activity against HeLa and B16 cells. Chromatographically obtained lipophilicity parameters were correlated with calculated logP values and IC(50) values. Principal component analysis identified the dominant pattern in the chromatographically obtained data. 2008 John Wiley & Sons, Ltd.

Optimization of the qualitative composition of liposomal drugs based on natural organomineral formations

NASA Astrophysics Data System (ADS)

Chzhu, O. P.; Shubenkova, E. G.

2017-08-01

Liposomal structures were developed on the basis of oil and water extracts of natural organomineral formations. These structures are natural compositions. The content of the main components in the preparations varies within the range of 20-25% of the lipophilic phase, 64-74% of the hydrophilic phase, 5-10% of the auxiliary component and the stabilizer on the phospholipid base is 1%. Phospholipids of natural origin were used as surface-active substances. The influence of hydrophilic and lipophilic auxiliary components on the content of neutral lipids in the surface lipid layer of the skin was studied. The developed preparations can be used as carriers of both hydrophilic and lipophilic active substances in pharmaceutical compositions, cosmetic and veterinary products on a natural basis.

Chemical basis for the phytotoxicity of N-aryl hydroxamic acids and acetanilide analogues.

PubMed

Bravo, Héctor R; Villarroel, Elisa; Copaja, Sylvia V; Argandoña, Victor H

2008-01-01

Germination inhibition activity of N-aryl hydroxamic acids and acetanilide analogues was measured on lettuce seeds (Lactuca sativa). Lipophilicity of the compounds was determined by HPLC. A correlation between lipophilicity values and percentage of germination inhibition was established. A model mechanism of action for auxin was used for analyzing the effect of the substituent at the alpha carbon atom (Ca) on the polarization of hydroxamic and amide functions in relation to the germination inhibition activity observed. Results suggest that the lipophilic and acidic properties play an important role in the phytotoxicity of the compounds. A test with the microalga Chlorella vulgaris was used to evaluate the potential herbicide activity of the hydroxamic acids and acetanilides.

Interfacial engineering using mixed protein systems: emulsion-based delivery systems for encapsulation and stabilization of β-carotene.

PubMed

Mao, Yingyi; Dubot, Marie; Xiao, Hang; McClements, David Julian

2013-05-29

Emulsion-based delivery systems are needed to encapsulate, protect, and deliver lipophilic bioactive components in the food, personal care, and pharmaceutical industries. The functional performance of these systems can be controlled by engineering the composition and structure of the interfacial layer coating the lipid droplets. In this study, interfacial properties were controlled using two globular proteins with widely differing isoelectric points: lactoferrin (LF: pI ≈ 8.5) and β-lactoglobulin (BLG: pI ≈ 5). Oil-in-water emulsions were prepared with different interfacial properties: [LF]-only; [BLG]-only; [LF]-[BLG]-(laminated); [BLG]-[LF]-(laminated); and [BLG/LF]-(mixed). The influence of pH, ionic strength, and temperature on the physical stability of β-carotene-enriched emulsions was investigated. [LF]-emulsions were stable to droplet aggregation from pH 2 to 9 (0 mM NaCl), but all other emulsions aggregated at intermediate pH values. [BLG]-emulsions aggregated at high salt levels (≥50 mM NaCl), but all other emulsions were stable (0 to 300 mM NaCl). [BLG/LF]-emulsions were unstable to heating (≥60 °C), but all other emulsions were stable (30 to 90 °C). Color fading due to β-carotene degradation occurred relatively quickly in [BLG]-emulsions (37 °C) but was considerably lower in all other emulsions, which was attributed to the ability of LF to bind iron or interact with β-carotene. This study provides useful information for designing emulsion-based delivery systems to encapsulate and protect bioactive lipids, such as carotenoids.

Development and characterization of controlled release polar lipid microparticles of candesartan cilexetil by solid dispersion

PubMed Central

Kamalakkannan, V; Puratchikody, A; Ramanathan, L

2013-01-01

Candesartan cilexetil (CC) is a newer class of angiotensin II receptor antagonist used for the treatment of hypertension. The solubility of the CC is very poor and its oral bioavailability is only 15%. The controlledrelease polar lipid microparticles of CC (formulations F1, F2, F3 and F4) were prepared using variable erodible lipophilic excipients like hydrogenated castor oil, stearic acid, cetostearyl alcohol and carnauba wax by fusion method. The particle sizes of polar lipid microparticles were less than 50 microns and they were irregular in shape. Drug content ranged between 98.96 ± 2.1 and 101.9 ± 1.6% were present in all the formulations. The formulation F3 showed better drug release throughout the study period in a controlled release manner. Moreover, the in vitro release showed that all the formulations were best fitted to Higuchi model. Accelerated stability studies indicated that there was no significant changes in the chemical and physical characteristics of the formulated drug product during initial and at the end of the study period. The FTIR and DSC studies showed that there was no interaction between the drug and lipophilic excipients and no polymorphic transitions in all formulations. The X-ray diffraction peak of solid dispersion indicated that the crystalline nature of CC disappeared and no new peaks could be observed, suggesting the absence of interaction between drug and excipients. PMID:24019822

Oxygen radical absorbance capacity (ORAC) of cyclodextrin-solubilized flavonoids, resveratrol and astaxanthin as measured with the ORAC-EPR method

PubMed Central

Sueishi, Yoshimi; Ishikawa, Misa; Yoshioka, Daisuke; Endoh, Nobuyuki; Oowada, Shigeru; Shimmei, Masashi; Fujii, Hirotada; Kotake, Yashige

2012-01-01

Recently, we proposed an oxygen radical absorbance capacity method that directly quantifies the antioxidant’s scavenging capacity against free radicals and evaluated the radical scavenging abilities for water soluble antioxidant compounds. In this study, we determined the radical scavenging abilities of lipophilic antioxidants which were solubilized by cyclodextrin in water. Commonly employed fluorescence-based method measures the antioxidant’s protection capability for the fluorescent probe, while we directly quantify free-radical level using electron paramagnetic resonance spin trapping technique. In addition, the spin trapping-based method adopted controlled UV-photolysis of azo-initiator for free radical generation, but in fluorescence-based method, thermal decomposition of azo-initiator was utilized. We determined the radical scavenging abilities of seven well-known lipophilic antioxidants (five flavonoids, resveratrol and astaxanthin), using methylated β-cyclodextrin as a solubilizer. The results indicated that the agreement between spin trapping-based and fluorescence-based values was only fair partly because of a large variation in the previous fluorescence-based data. Typical radical scavenging abilities in trolox equivalent unit are: catechin 0.96; epicatechin 0.94; epigallocatechin gallate 1.3; kaempferol 0.37; myricetin 3.2; resveratrol 0.64; and astaxanthin 0.28, indicating that myricetin possesses the highest antioxidant capacity among the compounds tested. We sorted out the possible causes of the deviation between the two methods. PMID:22448093

Oxygen radical absorbance capacity (ORAC) of cyclodextrin-solubilized flavonoids, resveratrol and astaxanthin as measured with the ORAC-EPR method.

PubMed

Sueishi, Yoshimi; Ishikawa, Misa; Yoshioka, Daisuke; Endoh, Nobuyuki; Oowada, Shigeru; Shimmei, Masashi; Fujii, Hirotada; Kotake, Yashige

2012-03-01

Recently, we proposed an oxygen radical absorbance capacity method that directly quantifies the antioxidant's scavenging capacity against free radicals and evaluated the radical scavenging abilities for water soluble antioxidant compounds. In this study, we determined the radical scavenging abilities of lipophilic antioxidants which were solubilized by cyclodextrin in water. Commonly employed fluorescence-based method measures the antioxidant's protection capability for the fluorescent probe, while we directly quantify free-radical level using electron paramagnetic resonance spin trapping technique. In addition, the spin trapping-based method adopted controlled UV-photolysis of azo-initiator for free radical generation, but in fluorescence-based method, thermal decomposition of azo-initiator was utilized. We determined the radical scavenging abilities of seven well-known lipophilic antioxidants (five flavonoids, resveratrol and astaxanthin), using methylated β-cyclodextrin as a solubilizer. The results indicated that the agreement between spin trapping-based and fluorescence-based values was only fair partly because of a large variation in the previous fluorescence-based data. Typical radical scavenging abilities in trolox equivalent unit are: catechin 0.96; epicatechin 0.94; epigallocatechin gallate 1.3; kaempferol 0.37; myricetin 3.2; resveratrol 0.64; and astaxanthin 0.28, indicating that myricetin possesses the highest antioxidant capacity among the compounds tested. We sorted out the possible causes of the deviation between the two methods.

Lifting properties of the alkamide fraction from the fruit husks of Zanthoxylum bungeanum.

PubMed

Artaria, C; Maramaldi, G; Bonfigli, A; Rigano, L; Appendino, G

2011-08-01

The fruits of various Zanthoxylum species are used as a spice in the Chinese and Japanese cuisine because of their delicate flavour and tingling properties. The lipophilic hydroxyalkamides hydroxy α- and β-sanshools (1a,b) have been identified as the tingling principles of these plants, and previous studies have validated a sanshool-rich lipophilic extract from the fruit husks of Z. bungeanum Maxim. (Zanthalene ® ) as an anti-itching cosmetic ingredient. Because tingling is a sort of 'paralytic pungency', and Zanthalene ® potently inhibits synaptic transmission, we have investigated its capacity to relax subcutaneous muscles and act as a topical lifting agent for wrinkles. An anti-wrinkles extract rich in spilanthol (2), a lipophilic alkamide having sensory properties similar to those of Zanthalene ® , was used as a reference. Short-term (lifting effect) and long-term (anti-wrinkle) improvements of skin roughness parameters were evaluated by both objectives' and subjectives' measurements. An immediate 'lifting' effect was observed with the sanshool-rich lipophilic extract, at dosages at which the reference alkamide extract was inactive in the objective assays. Limited desensitization after repeated application and good overall tolerability were observed, although a modest long-term anti-wrinkle effect was shown by both products. Taken together, these observations validate the use of sanshool-rich lipophilic extracts as an efficacious, immediate-action lifting agent, and exemplify the relevance of sensory observations to foster the development of innovative cosmetic ingredients. © 2011 The Authors. ICS © 2011 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Transport of ginkgolides with different lipophilicities based on an hCMEC/D3 cell monolayer as a blood-brain barrier cell model.

PubMed

Ma, Shuwei; Liu, Xingyan; Xu, Qingrun; Zhang, Xiantao

2014-10-02

In this report, the transport of ginkgolides with different lipophilicities was investigated using an hCMEC/D3 cell monolayer as a blood-brain barrier (BBB) cell model in vitro in an attempt to explain ginkgolide transport path mediated by lipophilicity. The log P values of ginkgolides were determined by measuring the distribution of the molecule between oil and water. Additionally, the cytotoxicity of ginkgolides on hCMEC/D3 cells was assayed with the MTT method. Ginkgolide contents were determined with an ultra performance liquid chromatograph equipped with an evaporative light scattering detector (ULPC-ELSD) method. Apparent permeability coefficients (Papp) and efflux ratios (PappBL→AP/PappAP→BL) were then calculated to describe the transport characteristics of ginkgolide. The transport of ginkgolide A, ginkgolide B, ginkgolide C, and ginkgolide J across the hCMEC/D3 cell monolayer was non-directional. Additionally, ginkgolide C transport on the cell monolayer was time- and concentration-dependent in the paracellular pathway controlled by cytochalasin D (a tight junction modulator). The transport of ginkgolide N, ginkgolide L, and ginkgolide K across the cell monolayer displayed clear directionality at low ginkgolide concentrations. This behavior indicated that the transport of ginkgolide N, ginkgolide L, and ginkgolide K was influenced by the transcellular pathway containing an efflux protein accompanied by the paracellular pathway for passive diffusion. Additionally, the transport of ginkgolide K was increased significantly by co-culturing with a P-gp inhibitor. These findings provide important information for elucidating ginkgolide transport pathways and may be beneficial for the design of ginkgolide molecules with high neuroprotective effects. Copyright © 2014 Elsevier Inc. All rights reserved.

Structure/activity relationships for the enhancement by electron-affinic drugs of the anti-tumour effect of CCNU.

PubMed Central

Workman, P.; Twentyman, P. R.

1982-01-01

Using a regrowth-delay assay, we investigated structure/activity relationships for the enhancement by electron-affinic agents of the anti-tumour effect of the nitrosourea CCNU against the KHT sarcoma in C3H mice. A series of neutral 2-nitroimidazoles similar in electron affinity but varying in octanol/water partition coefficient (PC) over 4 orders of magnitude (0.016- greater than 200, Misonidazole = 0.43) were examined at a fixed dose of 2.5 mmol/kg. A parabolic (quadratic) dependence of activity on log PC was observed. Analogues more hydrophilic than misonidazole (MISO) were inactive as were those with very high PCs (greater than 20). Those with PC 0.43--20 were usually more active than MISO, some considerably so. The fairly lipophilic 5-nitroimidazoles nimorazole and metronidazole (METRO) had similar activity to MISO, despite their reduced electron affinity. Two basic 2-nitroimidazoles more efficient as radiosensitizers in vitro likewise showed activity comparable to MISO. We also investigated several agents more electron-affinic than MISO, including some non-nitro compounds. Most were inactive at maximum tolerated doses, but nitrofurazone showed reasonable activity. Sensitizer dose-response curves were obtained for MISO, METRO and two of the most effective agents, benznidazole (Ro 07-1051) and Ro 07-1902. The two latter agents were both considerably more active than MISO at low doses (0.1--0.9 mmol/kg). These studies indicate that the structural features of electron-affinic agents responsible for the enhancement of KHT tumour response to CCNU, are quite different from those affecting radiosensitization, lipophilicity being particularly important. The microsomal enzyme-inhibitor SKF 525A increased the anti-tumour effect of CCNU, suggesting inhibition of CCNU metabolism as one possible mechanism contributing to chemosensitization by lipophilic electron-affinic agents in mice. PMID:7150475

The SPI1 Gene, Encoding a Glycosylphosphatidylinositol-Anchored Cell Wall Protein, Plays a Prominent Role in the Development of Yeast Resistance to Lipophilic Weak-Acid Food Preservatives▿

PubMed Central

Simões, T.; Mira, N. P.; Fernandes, A. R.; Sá-Correia, Isabel

2006-01-01

The Saccharomyces cerevisiae SPI1 gene encodes a member of the glycosylphosphatidylinositol-anchored cell wall protein family. In this work we show results indicating that SPI1 expression protects the yeast cell from damage caused by weak acids used as food preservatives. This is documented by a less extended period of adaptation to growth in their presence and by a less inhibited specific growth rate for a parental strain compared with a mutant with SPI1 deleted. Maximal protection exerted by Spi1p against equivalent concentrations of the various weak acids tested was registered for the more lipophilic acids (octanoic acid, followed by benzoic acid) and was minimal for acetic acid. Weak-acid adaptation was found to involve the rapid activation of SPI1 transcription, which is dependent on the presence of the Msn2p transcription factor. Activation of SPI1 transcription upon acetic acid stress also requires Haa1p, whereas this recently described transcription factor has a negligible role in the adaptive response to benzoic acid. The expression of SPI1 was found to play a prominent role in the development of yeast resistance to 1,3-β-glucanase in benzoic acid-stressed cells, while its involvement in acetic acid-induced resistance to the cell wall-lytic enzyme is slighter. The results are consistent with the notion that Spi1p expression upon weak-acid stress leads to cell wall remodeling, especially for the more lipophilic acids, decreasing cell wall porosity. Decreased cell wall porosity, in turn, reduces access to the plasma membrane, reducing membrane damage, intracellular acidification, and viability loss. PMID:16980434

Phytochemicals and antioxidant capacities in rice brans of different color.

PubMed

Min, Byungrok; McClung, Anna M; Chen, Ming-Hsuan

2011-01-01

Rice bran, a byproduct of the rice milling process, contains most of the phytochemicals. This study aimed at determining the concentrations of lipophilic, solvent-extractable (free), and cell wall-bound (bound) phytochemicals and their antioxidant capacities from brans of white, light brown, brown, purple, and red colors, and broccoli and blueberry for comparison. The concentrations of lipophilic antioxidants of vitamin E (tocopherol and tocotrienols) and γ-oryzanols were 319.67 to 443.73 and 3861.93 to 5911.12 μg/g bran dry weight (DW), respectively, and were not associated with bran color. The total phenolic, total flavonoid, and antioxidant capacities of ORAC (oxygen radical absorbance capacity), DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging, and iron-chelating in the free fraction were correlated with the intensity of bran color, while variations of these in the bound fraction were less than those in the free fraction among brans. Compounds in the bound fraction had higher antioxidant capacity of ORAC than DPPH, relative to those in the free fraction. The bound fraction of light-color brans contributed as much to its total ORAC as the free fraction. Total proanthocyanidin concentration was the highest in red rice bran, while total anthocyanin was highest in purple brans. The predominant anthocyanin was cyanidin-3-glucoside. Red and purple brans had several fold higher total phenolics and flavonoids as well as ORAC and DPPH, from both free and bound fractions, than freeze-dried blueberry and broccoli. These results indicate that rice brans are natural sources of hydrophilic and lipophilic phytochemicals for use in quality control of various food systems as well as for nutraceutical and functional food application.

Lipophilicity as a determinant of thiazolidinedione action in vitro: findings from BLX-1002, a novel compound without affinity to PPARs.

PubMed

Brunmair, Barbara; Staniek, Katrin; Lehner, Zsuzsanna; Dey, Debendranath; Bolten, Charles W; Stadlbauer, Karin; Luger, Anton; Fürnsinn, Clemens

2011-06-01

The pharmacology of thiazolidinediones (TZDs) seems to be driven not only by activation of peroxisome proliferator-activated receptor-γ (PPARγ), but also by PPARγ-independent effects on mitochondrial function and cellular fuel handling. This study portrayed such actions of the novel hydrophilic TZD compound BLX-1002 and compared them to those of conventional TZDs. Mitochondrial function and fuel handling were examined in disrupted rat muscle mitochondria, intact rat liver mitochondria, and specimens of rat skeletal muscle. BLX-1002 was superior to most other TZDs as an inhibitor of respiratory complex 1 in disrupted mitochondria, but had less effect than any other TZD on oxygen consumption by intact mitochondria and on fuel metabolism by intact tissue. The latter finding was obviously related to the hydrophilic properties of BLX-1002, because high potentials of individual TZDs to shift muscle fuel metabolism from the aerobic into the anaerobic pathway were associated with high ClogP values indicative of high lipophilicity and low hydrophilicity (e.g., % increase in lactate release induced by 10 μmol/l of respective compound: BLX-1002, ClogP 0.39, +10 ± 8%, not significant; pioglitazone, ClogP 3.53, +68 ± 12%, P < 0.001; troglitazone, ClogP 5.58, +157 ± 14%, P < 0.001). The observed specific properties of BLX-1002 could result from relatively strong direct affinity to an unknown mitochondrial target, but limited access to this target. Results suggest 1) that impairment of mitochondrial function and increased anaerobic fuel metabolism are unlikely to account for PPARγ-independent glucose lowering by BLX-1002, and 2) that higher lipophilicity of an individual TZD is associated with stronger acceleration of anaerobic glycolysis.

Correlations between chromatographic parameters and bioactivity predictors of potential herbicides.

PubMed

Janicka, Małgorzata

2014-08-01

Different liquid chromatography techniques, including reversed-phase liquid chromatography on Purosphere RP-18e, IAM.PC.DD2 and Cosmosil Cholester columns and micellar liqud chromatography with a Purosphere RP-8e column and using buffered sodium dodecyl sulfate-acetonitrile as the mobile phase, were applied to study the lipophilic properties of 15 newly synthesized phenoxyacetic and carbamic acid derivatives, which are potential herbicides. Chromatographic lipophilicity descriptors were used to extrapolate log k parameters (log kw and log km) and log k values. Partitioning lipophilicity descriptors, i.e., log P coefficients in an n-octanol-water system, were computed from the molecular structures of the tested compounds. Bioactivity descriptors, including partition coefficients in a water-plant cuticle system and water-human serum albumin and coefficients for human skin partition and permeation were calculated in silico by ACD/ADME software using the linear solvation energy relationship of Abraham. Principal component analysis was applied to describe similarities between various chromatographic and partitioning lipophilicities. Highly significant, predictive linear relationships were found between chromatographic parameters and bioactivity descriptors. © The Author [2013]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Photoimages and the release characteristics of lipophilic matrix tablets containing highly water-soluble potassium citrate with high drug loadings.

PubMed

Cao, Qing-Ri; Kim, Tae-Wan; Lee, Beom-Jin

2007-07-18

Two types of the carnauba wax-based lipophilic matrix tablet using spray-dried granules (SDT) or directly compressible powdered mixtures (DCT) were prepared for sustained release. The model drug was a highly water-soluble potassium citrate and loaded about 74% of the total tablet weight. The SDT slowly eroded and disintegrated during the release study without showing sustained release when the hydrophilic excipients were added. In contrast, the DCT was more efficient for sustained release. The release rate decreased with increasing carnauba wax concentration. In particular, the sustained release rate was markedly pronounced when the lipophilic stearyl alcohol and stearic acid were combined with the carnauba wax. The surface of the intact DCT appeared to be smooth and rusty. The DCT rose to the surface from the bottom of the vessel during the release test, and numerous pores and cracks with no signs of disintegration were also observed after the release test. The release profile was dependent on the formulation composition and preparation method of the matrix tablet. Diffusion-controlled leaching through the channels of the pores and cracks of the lipophilic matrix tablet (DCT) is a key to the sustained release.

A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin

DOE PAGES

Xia, Yifeng; Liu, Yi -Liang; Xie, Yonghua; ...

2014-11-19

Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not yet been successfully targeted. Here in this paper, we describe a combination therapy for treating these malignancies using two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of the KRAS and other small G-proteins critical for tumor growthmore » and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant NF-κB activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mTOR pathway, facilitated autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. Lastly, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations.« less

Inhibition of Na+−H+ exchange impairs receptor-mediated albumin endocytosis in renal proximal tubule-derived epithelial cells from opossum

PubMed Central

Gekle, Michael; Drumm, Karina; Mildenberger, Sigrid; Freudinger, Ruth; Gaßner, Birgit; Silbernagl, Stefan

1999-01-01

Receptor-mediated endocytosis is an important mechanism for transport of macromolecules and regulation of cell-surface receptor expression. In renal proximal tubules, receptor-mediated endocytosis mediates the reabsorption of filtered albumin. Acidification of the endocytic compartments is essential because it interferes with ligand-receptor dissociation, vesicle trafficking, fusion events and coat formation. Here we show that the activity of Na+−H+ exchanger isoform 3 (NHE3) is important for proper receptor-mediated endocytosis of albumin and endosomal pH homeostasis in a renal proximal tubular cell line (opossum kidney cells) which expresses NHE3 only. Depending on their inhibitory potency with respect to NHE3 and their lipophilicity, the NHE inhibitors EIPA, amiloride and HOE694 differentially reduced albumin endocytosis. The hydrophilic inhibitor HOE642 had no effect. Inhibition of NHE3 led to an alkalinization of early endosomes and to an acidification of the cytoplasm, indicating that Na+−H+ exchange contributes to the acidification of the early endosomal compartment due to the existence of a sufficient Na+ gradient across the endosomal membrane. Exclusive acidification of the cytoplasm with propionic acid or by removal of Na+ induced a significantly smaller reduction in endocytosis than that induced by inhibition of Na+−H+ exchange. Analysis of the inhibitory profiles indicates that in early endosomes and endocytic vesicles NHE3 is of major importance, whereas plasma membrane NHE3 plays a minor role. Thus, NHE3-mediated acidification along the first part of the endocytic pathway plays an important role in receptor-mediated endocytosis. Furthermore, the involvement of NHE3 offers new ways to explain the regulation of receptor-mediated endocytosis. PMID:10545138

Fine-tuned broad binding capability of human lipocalin-type prostaglandin D synthase for various small lipophilic ligands.

PubMed

Kume, Satoshi; Lee, Young-Ho; Nakatsuji, Masatoshi; Teraoka, Yoshiaki; Yamaguchi, Keisuke; Goto, Yuji; Inui, Takashi

2014-03-18

The hydrophobic cavity of lipocalin-type prostaglandin D synthase (L-PGDS) has been suggested to accommodate various lipophilic ligands through hydrophobic effects, but its energetic origin remains unknown. We characterized 18 buffer-independent binding systems between human L-PGDS and lipophilic ligands using isothermal titration calorimetry. Although the classical hydrophobic effect was mostly detected, all complex formations were driven by favorable enthalpic gains. Gibbs energy changes strongly correlated with the number of hydrogen bond acceptors of ligand. Thus, the broad binding capability of L-PGDS for ligands should be viewed as hydrophilic interactions delicately tuned by enthalpy-entropy compensation using combined effects of hydrophilic and hydrophobic interactions. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Structural correlation between lipophilicity and lipopolysaccharide-sequestering activity in spermine-sulfonamide analogs.

PubMed

Burns, Mark R; Jenkins, Scott A; Vermeulen, Nicolas M; Balakrishna, Rajalakshmi; Nguyen, Thuan B; Kimbrell, Matthew R; David, Sunil A

2006-12-15

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria, and play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. We had previously defined the pharmacophore necessary for small molecules to specifically bind and neutralize this complex carbohydrate. A series of aryl and aliphatic spermine-sulfonamide analogs were synthesized and tested in a series of binding and cell-based assays in order to probe the effect of lipophilicity on sequestration ability. A strong correlation was indeed found, supporting the hypothesis that endotoxin-neutralizing ability involves a lipophilic or membrane attachment event. The research discussed herein may be useful for the design of additional carbohydrate recognizing molecules and endotoxin-neutralizing drugs.

Design of fluorinated 5-HT(4)R antagonists: influence of the basicity and lipophilicity toward the 5-HT(4)R binding affinities.

PubMed

Fontenelle, Clement Q; Wang, Zhong; Fossey, Christine; Cailly, Thomas; Linclau, Bruno; Fabis, Frederic

2013-12-01

Analogues of potent 5-HT(4)R antagonists possessing a fluorinated N-alkyl chain have been synthesized in order to investigate the effect of the resulting change in basicity and lipophilicity on the affinity and selectivity profile. We demonstrate that for this series, the affinity is decreased with decreased basicity of the piperidine's nitrogen atom. In contrast, the resulting increase in lipophilicity has minimal impact on binding affinity and selectivity. 3,3,3-Trifluoropropyl and 4,4,4-trifluorobutyl derivatives 6d and 6e have shown to bind to the 5-HT(4)R while maintaining their pharmacological profile and selectivity toward other 5-HT receptors. Copyright © 2013 Elsevier Ltd. All rights reserved.

Improvement of the lipophilic-oxygen radical absorbance capacity (L-ORAC) method and single-laboratory validation.

PubMed

Watanabe, Jun; Oki, Tomoyuki; Takebayashi, Jun; Yamasaki, Koji; Takano-Ishikawa, Yuko; Hino, Akihiro; Yasui, Akemi

2013-01-01

We improved the procedure for lipophilic-oxygen radical absorbance capacity (L-ORAC) measurement for better repeatability and intermediate precision. A sealing film was placed on the assay plate, and glass vials and microdispensers equipped with glass capillaries were used. The antioxidant capacities of food extracts can be evaluated by this method with nearly the same precision as antioxidant solutions.

Radiopharmaceuticals for imaging the heart

DOEpatents

Green, Mark A.; Tsang, Brenda W.

1994-01-01

Radiopharmaceuticals for imaging myocardial tissues are prepared by forming lipophilic, cationic complexes of radioactive metal ions with metal chelating ligands comprising the Schiff base adducts of triamines and tetraamines with optionally substituted salicylaldehydes. The lipophilic, cationic, radioactive complexes of the invention exhibit high uptake and retention in myocardial tissues. Preferred gallium-68(III) complexes in accordance with this invention can be used to image the heart using positron emission tomography.

Pyclen Tri-n-butylphosphonate Ester as Potential Chelator for Targeted Radiotherapy: From Yttrium(III) Complexation to (90)Y Radiolabeling.

PubMed

Le Fur, Mariane; Beyler, Maryline; Lepareur, Nicolas; Fougère, Olivier; Platas-Iglesias, Carlos; Rousseaux, Olivier; Tripier, Raphaël

2016-08-15

The Y(3+) complex of PCTMB, the tri-n-butyl phosphonate ester of pyclen (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene), was synthesized as well as its Ho(3+) and Lu(3+) analogues. X-ray diffraction analyses revealed isomorphous dimeric M2(PCTMB)2·9H2O (M = Y, Ho, Lu) structures that crystallize in the centrosymmetric P1̅ triclinic space group. (1)H NMR and UV studies in aqueous solutions indicated that Y(3+) complexation is fast, being quantitative in 167 min at pH 3.8 and in 13 min at pH 5.5 (25 °C, acetate buffer, I = 0.150 M, [Y(3+)] = [PCTMB] = 0.2 mM). (1)H NMR DOSY and photon correlation spectroscopy experiments evidenced the formation of aggregates in chloroform with a bimodal distribution that changes slightly with concentration (11-24 and 240-258 nm). The behavior of the acid-assisted dissociation of the complex of Y(3+) with PCTMB was studied under pseudo-first-order conditions, and the half-life of the [Y(PCTMB)] complex in 0.5 M HCl at 25 °C was found to be 37 min, a value that decreases to 2.6 min in 5 M HCl. The Y(3+) complex of PCTMB is thermodynamically very stable, with a stability constant of log KY-PCTMB = 19.49 and pY = 16.7 measured by potentiometry. (90)Y complexation studies revealed fast radiolabeling kinetics; optimal radiolabeling conditions were obtained for (90)Y in acetate medium, PCTMB at 10(-4) to 10(-2) M in acetate buffer pH = 4.75, 15 min at 45-60 °C. In vitro stability studies in human serum showed that [(90)Y(PCTMB)] is quite stable, with about 90% of the activity still in the form of the radiotracer at 24 h and 80% from 48 h to 72 h. A comparison with other ligands such as PCTA, DOTA, and DTPA already used for in vivo application shows that [(90)Y(PCTMB)] is an interesting lipophilic and neutral analogue of these reference chelates for therapeutic applications in aqueous and nonaqueous media.

Lipophilic versus hydrophilic statin therapy for heart failure: a protocol for an adjusted indirect comparison meta-analysis

PubMed Central

2013-01-01

Background Statins are known to reduce cardiovascular morbidity and mortality in primary and secondary prevention studies. Subsequently, a number of nonrandomised studies have shown statins improve clinical outcomes in patients with heart failure (HF). Small randomised controlled trials (RCT) also show improved cardiac function, reduced inflammation and mortality with statins in HF. However, the findings of two large RCTs do not support the evidence provided by previous studies and suggest statins lack beneficial effects in HF. Two meta-analyses have shown statins do not improve survival, whereas two others showed improved cardiac function and reduced inflammation in HF. It appears lipophilic statins produce better survival and other outcome benefits compared to hydrophilic statins. But the two types have not been compared in direct comparison trials in HF. Methods/design We will conduct a systematic review and meta-analysis of lipophilic and hydrophilic statin therapy in patients with HF. Our objectives are: 1. To determine the effects of lipophilic statins on (1) mortality, (2) hospitalisation for worsening HF, (3) cardiac function and (4) inflammation. 2. To determine the effects of hydrophilic statins on (1) mortality, (2) hospitalisation for worsening HF, (3) cardiac function and (4) inflammation. 3. To compare the efficacy of lipophilic and hydrophilic statins on HF outcomes with an adjusted indirect comparison meta-analysis. We will conduct an electronic search of databases for RCTs that evaluate statins in patients with HF. The reference lists of all identified studies will be reviewed. Two independent reviewers will conduct the search. The inclusion criteria include: 1. RCTs comparing statins with placebo or no statin in patients with symptomatic HF. 2. RCTs that employed the intention-to-treat (ITT) principle in data analysis. 3. Symptomatic HF patients of all aetiologies and on standard treatment. 4. Statin of any dose as intervention. 5. Placebo or no statin arm as control. The exclusion criteria include: 1. RCTs involving cerivastatin in HF patients. 2. RCTs with less than 4 weeks of follow-up. Discussion We will perform an adjusted indirect comparison meta-analysis of lipophilic versus hydrophilic statins in patients with HF using placebo or no statin arm as common comparator. PMID:23618535

Pastes: what do they contain? How do they work?

PubMed

Juch, R D; Rufli, T; Surber, C

1994-01-01

Pastes are semisolid stiff preparations containing a high proportion of finely powdered material. Powders such as zinc oxide, titanium dioxide, starch, kaolin or talc are incorporated in high concentrations into a preferably lipophilic, greasy vehicle. A clinically distinctive feature which is generally attributed to pastes is the quality to absorb exudates by nature of the powder or other absorptive components. Reviewing the various pharmacopoeias serious doubts arise from the various formulas of pastes and their absorptive features. The zinc oxide pastes of the USP XXII, the DAB 10 and BP 88 (US, German and British pharmacopoeias). are composed of petrolatum, zinc oxide and starch. Petrolatum, a highly lipophilic, water-immiscible vehicle surrounds the powder particles preventing any absorption of water or exudates. The goal of our investigation was to test a simple experimental setting to characterize the clinically important absorptive feature of powders and pastes. The absorptive features of the powders were determined by the method of Enslin. The absorptive features of the paste preparations were calculated from the weight difference between the paste preparation before and after incubation with water using a simple standardized procedure. The absorptive features of titanium dioxide, zinc oxide, kaolin, corn starch and methylcellulose powder in pharmacopoeia quality were determined. Zinc oxide and kaolin powder showed the highest absorption of 1,000 mg water/g powder (100%). The water absorption of corn starch and titanium dioxide was 700 and 450 mg/g powder, respectively. The absorptive features of a series of paste preparations were studied in a simple experimental setting. The data show that two-phase pastes consisting of two immiscible components, one (the dispersed or inner phase; powder) being suspended in the other (the continuous or outer phase; lipophilic vehicle), have no absorptive features. In contrast, three-phase pastes consisting of a hydrophilic two-phase emulsion with high concentrations of incorporated powder (cream pastes) show considerable water uptake. We conclude that the classical two-phase pastes such as the zinc oxide pastes have no absorptive features. On the contrary, these formulations are highly occlusive. Therefore lipophilic pastes are only indicated when protection of intact skin against aggressive body exudates and humidity is required. The hydrophilic three-phase pastes or cream pastes show considerable water uptake and fulfil common expectations of pastes to dry the skin.

Photoinduced electron transfer across a molecular wall: coumarin dyes as donors and methyl viologen and TiO2 as acceptors.

PubMed

Porel, Mintu; Klimczak, Agnieszka; Freitag, Marina; Galoppini, Elena; Ramamurthy, V

2012-02-21

Coumarins C-153, C-480, and C-1 formed 1:2 (guest:host) complexes with a water-soluble cavitand having eight carboxylic acid groups (OA) in aqueous borate buffer solution. The complexes were photoexcited in the presence of electron acceptors (methyl viologen, MV(2+), or TiO(2)) to probe the possibility of electron transfer between a donor and an acceptor physically separated by a molecular wall. In solution at basic pH, the dication MV(2+) was associated to the exterior of the complex C-153@OA(2), as suggested by diffusion constants (~1.2 × 10(-6) cm(2)/s) determined by DOSY NMR. The fluorescence of C-153@OA(2) was quenched in the presence of increasing amounts of MV(2+) and Stern-Volmer plots of I(o)/I and τ(o)/τ vs [MV(2+)] indicated that the quenching was static. As per FT-IR-ATR spectra, the capsule C-153@OA(2) was bound to TiO(2) nanoparticle films. Selective excitation (λ(exc) = 420) of the above bound complex resulted in fluorescence quenching. When adsorbed on insulating ZrO(2) nanoparticle films, excitation of the complex resulted in a broad fluorescence spectrum centered at 500 nm and consistent with C-153 being within the lipophilic capsule interior. Consistent with the above results, colloidal TiO(2) quenched the emission while colloidal ZrO(2) did not.

Unraveling the Relative Importance of Oral and Dermal Contaminant Exposure in Reptiles: Insights from Studies Using the Western Fence Lizard (Sceloporus occidentalis)

PubMed Central

Weir, Scott M.; Talent, Larry G.; Anderson, Todd A.; Salice, Christopher J.

2014-01-01

Despite widespread recognition of significant data deficiencies, reptiles remain a relatively understudied taxon in ecotoxicology. To conduct ecological risk assessments on reptiles frequently requires using surrogate taxa such as birds, but recent research suggests that reptiles have significantly different exposure profiles and toxicant sensitivity. We exposed western fence lizards, Sceloporus occidentalis, to the same quantities of three model chemicals via oral (gavage) and dermal (ventral skin application) exposure for either 24 or 48 hours. Three phthalate esters (di-methyl phthalate [DMP], di-iso-butyl phthalate [DIBP], and di-n-octyl phthalate [DNOP]) were chosen as model chemicals because they represent a gradient of lipophilicity but are otherwise structurally similar. Overall, the more lipophilic phthalates (DIBP and DNOP) were found to have higher concentrations in tissues than the less lipophilic DMP. Significant differences in tissue concentrations between DIBP and DNOP were tissue-dependent, suggesting that delivery to a site of action following exposure is not only a simple function of lipophilicity. In dermal treatments, DMP usually had fewer detections (except in ventral skin samples), suggesting that lipophilicity (log Kow>2) is a requirement for uptake across the skin. In general, tissue residues were greater in oral treatments than dermal treatments (significant in adipose and liver tissue), but differences were driven strongly by differences in DMP which did not appear to be absorbed well across skin. When differences in tissue residue concentrations between oral and dermal exposure did occur, the difference was not drastic. Taken together these results suggest that dermal exposure should be considered in risk assessments for reptilian receptors. Dermal exposure may be an especially important route for reptiles as their ectothermic physiology translates to lower energetic demands and dietary exposure compared to birds and mammals. PMID:24941063

Unraveling the relative importance of oral and dermal contaminant exposure in reptiles: insights from studies using the western fence lizard (Sceloporus occidentalis).

PubMed

Weir, Scott M; Talent, Larry G; Anderson, Todd A; Salice, Christopher J

2014-01-01

Despite widespread recognition of significant data deficiencies, reptiles remain a relatively understudied taxon in ecotoxicology. To conduct ecological risk assessments on reptiles frequently requires using surrogate taxa such as birds, but recent research suggests that reptiles have significantly different exposure profiles and toxicant sensitivity. We exposed western fence lizards, Sceloporus occidentalis, to the same quantities of three model chemicals via oral (gavage) and dermal (ventral skin application) exposure for either 24 or 48 hours. Three phthalate esters (di-methyl phthalate [DMP], di-iso-butyl phthalate [DIBP], and di-n-octyl phthalate [DNOP]) were chosen as model chemicals because they represent a gradient of lipophilicity but are otherwise structurally similar. Overall, the more lipophilic phthalates (DIBP and DNOP) were found to have higher concentrations in tissues than the less lipophilic DMP. Significant differences in tissue concentrations between DIBP and DNOP were tissue-dependent, suggesting that delivery to a site of action following exposure is not only a simple function of lipophilicity. In dermal treatments, DMP usually had fewer detections (except in ventral skin samples), suggesting that lipophilicity (log Kow>2) is a requirement for uptake across the skin. In general, tissue residues were greater in oral treatments than dermal treatments (significant in adipose and liver tissue), but differences were driven strongly by differences in DMP which did not appear to be absorbed well across skin. When differences in tissue residue concentrations between oral and dermal exposure did occur, the difference was not drastic. Taken together these results suggest that dermal exposure should be considered in risk assessments for reptilian receptors. Dermal exposure may be an especially important route for reptiles as their ectothermic physiology translates to lower energetic demands and dietary exposure compared to birds and mammals.

Lipophilicity plays a major role in modulating the inhibition of monoamine oxidase B by 7-substituted coumarins.

PubMed

Carotti, Angelo; Altomare, Cosimo; Catto, Marco; Gnerre, Carmela; Summo, Luciana; De Marco, Agostino; Rose, Sarah; Jenner, Peter; Testa, Bernard

2006-02-01

A series of coumarin derivatives (1-22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC(50) values in the micromolar to low-nanomolar range. A structure-activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r(2)=0.72) between pIC(50) and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1 h after intraperitoneal administration of high doses (100 and 300 mumol kg(-1)), revealing its ability to cross the blood-brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues.

Possible mechanism for drug retardation from glyceryl monostearate matrix system.

PubMed

Peh, K K; Wong, C F; Yuen, K H

2000-04-01

Lipophilicity was evaluated as a possible mechanism for drug retardation from a glyceryl monostearate matrix system. Lipophilicity of the glyceryl monostearate matrix system was studied using contact angle measurement of water droplets on the surface of compressed disks, extrudate ascension of water, and movement of water through a powder mixture packed in a high-performance liquid chromatographic (HPLC) column. Increase in glyceryl monostearate content resulted in an increase in water droplet contact angle, decrease in the rate of water ascending the extrudate, and increase in the pressure values as a function of flow rate of water moving through the powder mixture. These could be due to the increase in lipophilicity of the matrix, rendering the matrix less wettable. As a result, the rate of water penetration into the matrix decreased, and the drug release could be sustained.

Analysis of Moms Across America report suggesting bioaccumulation of glyphosate in U.S. mother's breast milk: Implausibility based on inconsistency with available body of glyphosate animal toxicokinetic, human biomonitoring, and physico-chemical data.

PubMed

Bus, James S

2015-12-01

The non-peer-reviewed biomonitoring report published online by Moms Across America (MAA; Honeycutt and Rowlands, 2014) does not support the conclusion that glyphosate concentrations detected in a limited number of urine samples from women, men and children, or breast milk from nursing mothers, pose a health risk to the public, including nursing children. Systemically absorbed doses of glyphosate estimated from the MAA urine biomonitoring data and from other published biomonitoring studies indicate that daily glyphosate doses are substantially below health protective reference standards (ADIs; RfDs) established by regulatory agencies. The MAA report also suggested that detection of relatively high glyphosate concentrations in breast milk in 3 of 10 sampled women raised a concern for bioaccumulation in breast milk. However, the breast milk concentrations reported by MAA are highly implausible when considered in context to low daily systemic doses of glyphosate estimated from human urine biomonitoring data, and also are inconsistent with animal toxicokinetic data demonstrating no evidence of retention in tissues or milk after single- or multiple-dose glyphosate treatment. In addition, toxicokinetic studies in lactating goats have shown that glyphosate does not partition into milk at concentrations greater than blood, and that only a very small percentage of the total administered dose (<0.03%) is ultimately excreted into milk. The toxicokinetic studies also indicate that human glyphosate exposures estimated from urine biomonitoring fall thousands-of-fold short of external doses capable of producing blood concentrations sufficient to result in the breast milk concentrations described in the MAA report. Finally, in contrast to highly lipophilic compounds with bioaccumulation potential in breast milk, the physico-chemical properties of glyphosate indicate that it is highly hydrophilic (ionized) at physiological pH and unlikely to preferentially distribute into breast milk. Copyright © 2015 Elsevier Inc. All rights reserved.

Radiopharmaceuticals for imaging the heart

DOEpatents

Green, M.A.; Tsang, B.W.

1994-06-28

Radiopharmaceuticals for imaging myocardial tissues are prepared by forming lipophilic, cationic complexes of radioactive metal ions with metal chelating ligands comprising the Schiff base adducts of triamines and tetraamines with optionally substituted salicylaldehydes. The lipophilic, cationic, radioactive complexes of the invention exhibit high uptake and retention in myocardial tissues. Preferred gallium-68(III) complexes in accordance with this invention can be used to image the heart using positron emission tomography. 6 figures.

Ocular Drug Delivery through pHEMA-Hydrogel Contact Lenses Co-Loaded with Lipophilic Vitamins

NASA Astrophysics Data System (ADS)

Lee, Dasom; Cho, Seungkwon; Park, Hwa Sung; Kwon, Inchan

2016-09-01

Ocular drug delivery through hydrogel contact lenses has great potential for the treatment of ocular diseases. Previous studies showed that the loading of lipophilic vitamin E to silicone-hydrogel contact lenses was beneficial in ocular drug delivery. We hypothesized that vitamin E loading to another type of popular hydrogel contact lenses, pHEMA-hydrogel contact lenses, improves ocular drug delivery by increasing the drug loading or the duration of drug release. Loading of vitamin E to pHEMA-hydrogel contact lenses significantly increased the loading of a hydrophilic drug surrogate (Alexa Fluor 488 dye) and two hydrophilic glaucoma drugs (timolol and brimonidine) to the lenses by 37.5%, 19.1%, and 18.7%, respectively. However, the release duration time was not significantly altered. Next, we hypothesized that the lipophilic nature of vitamin E attributes to the enhanced drug loading. Therefore, we investigated the effects of co-loading of another lipophilic vitamin, vitamin A, on drug surrogate delivery. We found out that vitamin A loading also increased the loading of the drug surrogate to pHEMA-hydrogel contact lenses by 30.3%. Similar to vitamin E loading, vitamin A loading did not significantly alter the release duration time of the drug or drug surrogate.

Effect of a high-fat meal on absorption and disposition of lipophilic compounds: the importance of degree of association with triglyceride-rich lipoproteins.

PubMed

Gershkovich, Pavel; Hoffman, Amnon

2007-09-01

Following a high-fat meal, triglyceride-rich lipoproteins (TRL) are assembled in the gut and absorbed via the lymph into the blood circulation, producing a temporal hyperlipidemia. The purpose of this study is to verify the hypothesis that this transient acute postprandial hyperlipidemia affects the pharmacokinetics of lipophilic drugs on both absorption and disposition levels by the same underlying mechanism, namely the association of active lipophilic compounds with TRL in the plasma (disposition) or within the enterocyte (lymphatic transport). This concept was assessed in rats using two model compounds, DDT with high affinity to chylomicrons and diazepam which does not bind to chylomicrons. Oral administration of peanut oil significantly increased the AUC of plasma DDT concentrations following its IV bolus administration in comparison to a water treated group. On the other hand, the AUC of diazepam following IV bolus administration was the same in oil and water treated rats. While DDT is known to have significant lymphatic bioavailability, diazepam has negligible intestinal lymphatic transport (0.014+/-0.004% of a given dose). In conclusion, lipophilic molecules that bind extensively to TRL will be prone to both intestinal lymphatic transport and to post-absorptive changes in disposition (decrease in clearance and volume of distribution) following a high-fat meal.

Lipophilic organic pollutants induce changes in phospholipid and membrane protein composition leading to Vero cell morphological change.

PubMed

Liao, Ting T; Wang, Lei; Jia, Ru W; Fu, Xiao H; Chua, Hong

2014-01-01

Membrane damage related to morphological change in Vero cells is a sensitive index of the composite biotoxicity of trace lipophilic chemicals. However, judging whether the morphological change in Vero cells happens and its ratio are difficult because it is not a quantitative characteristic. To find biomarkers of cell morphological change for quantitatively representing the ratio of morphological changed cell, the mechanism of cell membrane damage driven by typical lipophilic chemicals, such as trichlorophenol (TCP) and perfluorooctanesulphonate (PFOS), was explored. The ratio of morphologically changed cells generally increased with increased TCP or PFOS concentrations, and the level of four major components of phospholipids varied with concentrations of TCP or PFOS, but only the ratio of phosphatidylcholine (PC)/phosphatidylethanolamine (PE) decreased regularly as TCP or PFOS concentrations increased. Analysis of membrane proteins showed that the level of vimentin in normal cell membranes is high, while it decreases or vanishes after TCP exposure. These variations in phospholipid and membrane protein components may result in membrane leakage and variation in rigid structure, which leads to changes in cell morphology. Therefore, the ratio of PC/PE and amount of vimentin may be potential biomarkers for representing the ratio of morphological changed Vero cell introduced by trace lipophilic compounds, thus their composite bio-toxicity.

A new concept for risk assessment of the hazards of non-genotoxic chemicals--electronmicroscopic studies of the cell surface. Evidence for the action of lipophilic chemicals on the Ca2+ signaling system.

PubMed

Gartzke, J; Lange, K; Brandt, U; Bergmann, J

1997-06-20

Recently, we presented evidence for the localization of components of the cellular Ca2+ signaling pathway in microvilli. On stimulation of this pathway, microvilli undergo characteristic morphological changes which can be detected by scanning electron microscopy (SEM) of the cell surface. Here we show that both receptor-mediated (vasopressin) and unspecific stimulation of the Ca2+ signaling system by the lipophilic tumor promoters thapsigargin (TG) and phorbolmyristateacetate (PMA) are accompanied by the same type of morphological changes of the cell surface. Since stimulated cell proliferation accelerates tumor development and sustained elevation of the intracellular Ca2+ concentrations is a precondition for stimulated cell proliferation, activated Ca2+ signaling is one possible mechanism of non-genomic tumor promotion. Using isolated rat hepatocytes we show that all tested lipophilic chemicals with known tumor promoter action, caused characteristic microvillar shape changes. On the other hand, lipophilic solvents that were used as differentiating agents in cell cultures such as dimethylsulfoxide (DMSO) and dimethylformamide also, failed to change the microvillar shapes. Instead DMSO stabilized the original appearance of microvilli. The used technique provides a convenient method for the evaluation of non-genomic carcinogenicity of chemicals prior to their industrial application.

Biological activity of aldose reductase and lipophilicity of pyrrolyl-acetic acid derivatives

NASA Astrophysics Data System (ADS)

Kumari, A.; Kumari, R.; Kumar, R.; Gupta, M.

2011-12-01

Quantitative Structure-Activity Relationship modeling is a powerful approach for correlating an organic compound to its lipophilicity. In this paper QSAR models are established for estimation of correlation of the lipophilicity of a series of pyrrolyl-acetic acid derivatives, inhibitors of the aldose reductase enzyme, in the n-octanol-water system with biological activity of aldose reductase. Lipophilicity, expressed by the logarithm of n-octnol-water partition coefficient log P and biological activity of aldose reductase inhibitory activity by log it. Result obtained by QSAR modeling of compound series reveal a definite trend in biological activity and a further improvement in quantitative relationships are established if, beside log P, Hammett electronic constant σ and connectivity index chi-3 (3 χ) term included in the regression equation. The tri-parametric model with log P, 3 χ and σ as correlating parameters have been found to be the best which gives a variance of 87% ( R 2 = 0.8743). A compound has been found to be serious outlier and when the same has been excluded the model explains about 94% variance of the data set ( R 2 = 0.9447). The topological index (3 χ) has been found to be a good parameter for modeling the biological activity.

Enhancing effect of alpha-hydroxyacids on "in vitro" permeation across the human skin of compounds with different lipophilicity.

PubMed

Copoví, A; Díez-Sales, O; Herráez-Domínguez, J V; Herráez-Domínguez, M

2006-05-11

The percutaneous penetration-enhancing effects of glycolic acid, lactic acid and sodium lauryl sulphate through the human epidermis was investigated using 5-fluorouracil as a hydrophilic model permeant and three compounds belonging to the phenylalcohols: 2-phenyl-ethanol, 4-phenyl-butanol and 5-phenyl-pentanol. The lipophilicity values of the compounds ranged from log Poct -0.95 to 2.89. The effect of the enhancer concentration was also studied. Skin pretreatment with aqueous solutions of the three enhancers did not increase the permeability coefficient of the most lipophilic compound (log Poct = 2.89). For the other compounds assayed, the increase in the permeability coefficients depended on the concentration used in skin pretreatment, and on the lipophilicity of the compounds tested-and was always greater for the most hydrophilic compound (5-fluorouracil), for which lactic acid exerted a greater enhancer effect than glycolic acid or sodium lauryl sulphate. Primary irritation testing of the three enhancers was also carried out at the two concentrations used in skin pretreatment for diffusional experiments (1% and 5%, w/w). The least irritant capacity corresponded to lactic acid; consequently, this alpha-hydroxyacid could be proposed as a percutaneous penetration enhancer for hydrophilic molecules that are of interest for transdermal administration.

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity.

PubMed

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M

2016-07-20

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (sc) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. Their ease and efficiency make double-click helix stabilization chemistries a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control sc absorption and clearance rates to customize plasma pharmacokinetics.

An all-solid-state reference electrode based on the layer-by-layer polymer coating.

PubMed

Kwon, Nak-Hyun; Lee, Kyung-Sun; Won, Mi-Sook; Shim, Yoon-Bo

2007-09-01

A solid-state reference electrode (SSRE) was fabricated by layering a silicone rubber (SR) film containing KCl on an AgCl surface, then a perfluorinated ionomer film, and finally a polyurethane-based membrane containing an ionophore, a lipophilic ionic additive, and a plasticizer, respectively. The addition of SiCl4 to the polyurethane-based membrane layer enhanced the strength of the membrane in an aqueous solution. The morphologies of the membranes were studied separately by SEM. The fabrication of the Ag/AgCl electrode through this layer-by-layer polymer coating improved the electrode stability enormously. In addition, the potential drift of the SSRE according to the pH of the medium was minimized by introducing a H+-ion-selective ionophore (tridodecylamine; TDDA) into the outmost polymer membrane. The cyclic voltammetric and potentiometric responses using the SSRE and a conventional reference electrode, respectively, were consistent. The SSRE exhibited little potential variation even in the case of the addition of very high concentrations of various salts, such as Na salicylate, LiCl, KCl, CaCl2, MgCl2, KNO3, NaCl, and NaHCO3. The practicability of the proposed SSRE was tested for the determination of blood pH and pCO2 in a flow cell system. The SSRE fabricated in the present study was stable over two years.

CE-UV for the characterization of passion fruit juices provenance by amino acids profile with the aid of chemometric tools.

PubMed

Passos, Heloisa Moretti; Cieslarova, Zuzana; Simionato, Ana Valéria Colnaghi

2016-07-01

A separation method was developed in order to quantify free amino acids in passion fruit juices using CE-UV. A selective derivatization reaction with FMOC followed by MEKC analysis was chosen due to the highly interconnected mobilities of the analytes, enabling the separation of 22 amino acids by lipophilicity differences, as will be further discussed. To achieve such results, the method was optimized concerning BGE composition (concentrations, pH, and addition of organic modifier) and running conditions (temperature and applied voltage). The optimized running conditions were: a BGE composed by 60 mmol/L borate buffer at pH 10.1, 30 mmol/L SDS and 5 % methanol; running for 40 min at 23°C and 25 kV. The method was validated and applied on eight brands plus one fresh natural juice, detecting 12 amino acids. Quantification of six analytes combined with principal component analysis was capable to characterize different types of juices and showed potential to detect adulteration on industrial juices. Glutamic acid was found to be the most concentrated amino acid in all juices, exceeding 1 g/L in all samples and was also crucial for the correct classification of a natural juice, which presented a concentration of 22 g/L. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Stability of Fentanyl Citrate in Polyolefin Bags.

PubMed

Donnelly, Ronald F

2016-01-01

Fentanyl is used to manage pain because it is a potent lipophilic opiate agonist. The stability of fentanyl in polyolefin bags when diluted to either 10 µg/mL or 50 µg/mL with sodium chloride 0.9% has not been studied. The chemical stability of fentanyl 50 µg/mL packaged in polyvinyl chloride bags has been studied, however, the stability in polyolefin bags is lacking. Polyolefin bags were aseptically filled with either 10-µg/mL or 50-µg/mL fentanyl solution. Containers were then stored at either 5°C and protected from light or 22°C and exposed to light for 93 days. Fentanyl peaks were monitored using a stability-indicatin high-performance liquid chromatographic method. Changes to color, clarity, and pH were also monitored. There were no signs of chemical degradation of fentanyl packaged in polyolefin bags at either 5°C or 22°C after storage for 93 days. Over the course of the study, all solutions remained colorless and clear. The pH showed a slight decrease during the 93 days of storage. The stability of both undiluted (50-µg/mL) and diluted (10-µg/mL) fentanyl solutions when packaged in polyolefin bags was 93 days when stored at either 5°C or 22°C. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Analytical requirements, perspectives and limits of immunological methods for drugs in hair.

PubMed

Cassani, M; Spiehler, V

1993-12-01

The analytical requirements for analysis of drugs in hair are sensitivity in the range of picograms per milligram of hair, specificity for lipophilic drugs and absence of matrix effects with hair digests. These requirements are met by immunoassays which are also inexpensive, rapid and easy to use. However, in applying immunoassays to hair testing, certain limitations of the assay and of interpretation of assay results should be kept in perspective. These limitations are illustrated in this review with examples of the analysis of opiates in hair from patients and opiate addicts. The first requirement for immunological analysis of hair digests is that the digest must not denature the antibody proteins of the immunoassay reagents. For this reason enzymatic digests are better for immunological assay than chemical digests. Strongly acidic or alkaline digests must be brought to a neutral pH before immunoassay. Immunoassays used for analysis of hair should be calibrated with spiked hair digest standards to correct for possible matrix effects. The second requirement is that the immunoassay have the sensitivity and specificity to detect the drug in hair. Drugs of abuse are found in hair in the range of 10 pg-10 ng/mg hair. Radioimmunoassays are capable of detection and quantitation in this concentration range. Although the mechanism of drug incorporation into hair is not known, it is now apparent that primarily the parent drug and lipophilic metabolites are found in hair. For example, the ratio of cocaine/benzoylecgonine averages 10 (range 2-50) in published reports of analysis of hair from cocaine users. Therefore, immunoassays which are highly sensitive for the parent drug are required and results of immunoassays should be expressed as equivalents. When spiking standards for calibration of hair digest immunoassays, parent drug known to be present in hair should be used, e.g. cocaine not benzoylecgonine. With immunoassays which are specific for the lipophilic metabolite found in hair such as 6-MAM, differential radioimmunoassay can be used to discriminate between medical and illicit sources for the opiate drugs found in hair. Because of the low concentrations of drugs encountered in hair, immunoassays for hair have been used at cutoff concentrations at their limits of detection. The limit of detection (LOD) has been determined by calculating the mean and standard deviation (S.D.) for the assay response for a number of negative hair samples. The cutoff was then set at a distance of 2, 3, or 5 S.D.s from the mean response.(ABSTRACT TRUNCATED AT 400 WORDS)

Diverse human skin fungal communities in children converge in adulthood

PubMed Central

Jo, Jay-Hyun; Deming, Clayton; Kennedy, Elizabeth A.; Conlan, Sean; Polley, Eric C.; Ng, Weng-lan; Segre, Julia A.; Kong, Heidi H.

2017-01-01

Understanding the skin mycobiome (fungal communities) is important because both commensal and pathogenic fungi can drive cutaneous disease depending on host status and body sites, including the scalp, feet, and groin. Interestingly, age may also affect skin fungal infections as certain dermatophytoses (i.e. tinea capitis) are more frequent in children than adults. We previously described the skin mycobiomes in healthy adults, showing lipophilic fungi Malassezia predominate in most skin sites. Since children have less sebaceous skin before puberty, we compared the fungal communities of primary clinical samples from healthy children and adults, based on sequencing of a fungal phylogenetic marker. While Malassezia predominated on trunk, head and arm skin of adults (age 20s–30s), children (age <14) had more diverse fungal communities, for example, Eurotiomycetes which includes common dermatophytes. Species-level classification showed M. globosa predominated in children. Collectively, our findings indicate that prepubertal skin is colonized by diverse fungi, whereas adult skin is predominantly obligatory lipophilic Malassezia, suggesting that fungal communities on skin profoundly shift during puberty. Mycobiome shifts during puberty are likely due to alterations in sebaceous gland activation and sebum composition. This study provides a foundational framework for studies investigating interactions between fungi, skin, and pediatric dermatophytosis. PMID:27476723

Vehicle influence on permeation through intact and compromised skin.

PubMed

Gujjar, Meera; Banga, Ajay K

2014-09-10

The purpose of this study was to compare the transdermal permeation of a model compound, diclofenac diethylamine, from a hydrophilic and lipophilic vehicle across in vitro models simulating compromised skin. Mineral oil served as a lipophilic vehicle while 10mM phosphate buffered saline served as a hydrophilic vehicle. Compromised skin was simulated by tape stripping, delipidization, or microneedle application and compared with intact skin as a control. Transepidermal water loss was measured to assess barrier function. Skin compromised with tape stripping and delipidization significantly (p<0.05) increased permeation of diclofenac diethylamine compared to intact and microneedle treated skin with phosphate buffered saline vehicle. A similar trend in permeation was observed with mineral oil as the vehicle. For both vehicles, permeation across skin increased in the same order and correlated with degree of barrier impairment as indicated by transepidermal water loss values: intact

Valorization of antioxidants extracted from olive mill wastewater.

PubMed

Aissa, Imen; Kharrat, Nadia; Aloui, Fatma; Sellami, Mohamed; Bouaziz, Mohamed; Gargouri, Youssef

2017-07-01

Antioxidants are highly important gradients used to preserve cosmetic products and reduce the effect of oxidative stress on the skin. The present work explores the possibility of using phenolic compounds of olive mill wastewater (OMW) as effective alternatives to the commercial antioxidants used in cosmetic formulations deemed by their allergic and carcinogenic effects. Esterification of tyrosol and hydroxytyrosol extracted from OMW with various fatty acids was conducted using Novozyme 435 lipase as a biocatalyst. Upon synthesis, butyrate, caprate, laurate, and palmitate tyrosyl and hydroxytyrosyl esters were isolated and evaluated for their antioxidant and antibacterial activities. Results showed that laurate derivatives are the most efficient in preventing lipid oxidation and inhibiting growth of pathogenic strains. In the prospective of industrial use, laurate tyrosyl and hydroxytyrosyl derivatives were incorporated in a formulation of moisturizer to substitute the commercial antioxidant butylated hydroxyltoluene. Oleuropein, extracted from olive leaves powder, was also tested as an antiaging ingredient in cosmetic formulations. The evaluation of physicochemical, microbiological, and sensorial properties of the new cosmetic products indicated that oleuropein and lipophilic derivatives do not affect the properties of the standard formulation. Oleuropein and lipophilic derivatives can be added as active ingredients to stabilize cosmetic preparations. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

Selective removal of organochlorine pesticides (OCPs) from aqueous solution by triolein-embedded composite adsorbent.

PubMed

Ru, J; Liu, H J; Qu, J H; Wang, A M; Dai, R H; Wang, Z J

2007-01-01

A novel composite adsorbent (CA-T) was used for the selective removal of organochlorine pesticides (OCPs) from aqueous solution. The adsorbent was composed of the supporting activated carbon and the surrounding triolein-embedded cellulose acetate membrane. Scanning electron microscopy (SEM), N2 adsorption isotherms and fluorescence methods were used to characterize the physicochemical properties of CA-T. Triolein was perfectly embedded in the cellulose acetate membrane and deposited on the surface of activated carbon. The adsorbent was stable in water and no triolein leakage was detected during the test periods. Some organochlorine pesticides (OCPs), such as dieldrin, endrin, aldrin, and heptachlor epoxide, were used as model contaminants and removed by CA-T in laboratory batch experiments. The adsorption isotherm followed the Freundlich equation and the kinetic data fitted well to the pseudo-second-order reaction model. Results also indicated that CA-T appeared to be a promising adsorbent with good selectivity and satisfactory removal rate for lipophilic OCPs from aqueous solutions when present in trace amounts. The adsorption rate and removal efficiency for lipophilic OCPs were positively related to their octanol-water partition coefficients (log K(ow)). Lower residual concentrations of OCPs were achieved when compared to granular activated carbon (GAC).

Model of transient drug diffusion across cornea.

PubMed

Zhang, Wensheng; Prausnitz, Mark R; Edwards, Aurélie

2004-09-30

A mathematical model of solute transient diffusion across the cornea to the anterior chamber of the eye was developed for topical drug delivery. Solute bioavailability was predicted given solute molecular radius and octanol-to-water distribution coefficient (Phi), ocular membrane ultrastructural parameters, tear fluid hydrodynamics, as well as solute distribution volume (Vd) and clearance rate (Cla) in the anterior chamber. The results suggest that drug bioavailability is primarily determined by solute lipophilicity. In human eyes, bioavailability is predicted to range between 1% and 5% for lipophilic molecules (Phi>1), and to be less than 0.5% for hydrophilic molecules (Phi<0.01). The simulations indicate that the distribution coefficient that maximizes bioavailability is on the order of 10. It was also found that the maximum solute concentration in the anterior chamber (Cmax) and the time needed to reach Cmax significantly depend on Phi, Vd, and Cla. Consistent with experimental findings, model predictions suggest that drug bioavailability can be increased by lowering the conjunctival-to-corneal permeability ratio and reducing precorneal solute drainage. Because of its mechanistic basis, this model will be useful to predict drug transport kinetics and bioavailability for new compounds and in diseased eyes.

Cupric ion reducing antioxidant capacity assay for antioxidants in human serum and for hydroxyl radical scavengers.

PubMed

Apak, Reşat; Güçlü, Kubilay; Ozyürek, Mustafa; Bektaşoğlu, Burcu; Bener, Mustafa

2010-01-01

Tests measuring the combined antioxidant effect of the nonenzymatic defenses in biological fluids may be useful in providing an index of the organism's capability to counteract reactive species known as pro-oxidants, resist oxidative damage, and combat oxidative stress-related diseases. The selected chromogenic redox reagent for the assay of human serum should be easily accessible, stable, selective, and respond to all types of biologically important antioxidants such as ascorbic acid, alpha-tocopherol, beta-carotene, reduced glutathione (GSH), uric acid, and bilirubin, regardless of chemical type or hydrophilicity. Our recently developed cupric reducing antioxidant capacity (CUPRAC) spectrophotometric method for a number of polyphenols and flavonoids using the copper(II)-neocuproine reagent in ammonium acetate buffer is now applied to a complete series of plasma antioxidants for the assay of total antioxidant capacity of serum, and the resulting absorbance at 450 nm is recorded either directly (e.g., for ascorbic acid, alpha-tocopherol, and glutathione) or after incubation at 50 degrees C for 20 min (e.g., for uric acid, bilirubin, and albumin), quantitation being made by means of a calibration curve. The lipophilic antioxidants, alpha-tocopherol and beta-carotene, are assayed in dichloromethane. Lipophilic antioxidants of serum are extracted with n-hexane from an ethanolic solution of serum subjected to centrifugation. Hydrophilic antioxidants of serum are assayed in the centrifugate after perchloric acid precipitation of proteins. The CUPRAC molar absorptivities, linear ranges, and TEAC (trolox equivalent antioxidant capacity) coefficients of the serum antioxidants are established, and the results are evaluated in comparison with the findings of the ABTS/TEAC reference method. The intra- and inter-assay coefficients of variation (CVs) are 0.7 and 1.5%, respectively, for serum. The CUPRAC assay proved to be efficient for glutathione and thiol-type antioxidants, for which the FRAP (ferric reducing antioxidant potency) test is basically nonresponsive. The additivity of absorbances of all the tested antioxidants confirmed that antioxidants in the CUPRAC test do not chemically interact among each other so as to cause an intensification or quenching of the theoretically expected absorbance, and that a total antioxidant capacity (TAC) assay of serum is possible. As a distinct advantage over other electron-transfer based assays (e.g., Folin, FRAP, ABTS, DPPH), CUPRAC is superior in regard to its realistic pH close to the physiological pH, favorable redox potential, accessibility and stability of reagents, and applicability to lipophilic antioxidants as well as hydrophilic ones. The CUPRAC procedure can also assay hydroxyl radicals, being the most reactive oxygen species (ROS). As a more convenient, efficient, and less costly alternative to HPLC/electrochemical detection techniques and to the nonspecific, low-yield TBARS test, we use p-aminobenzoate, 2,4- and 3,5-dimethoxybenzoate probes for detecting hydroxyl radicals generated from an equivalent mixture of [Fe(II)+EDTA] with hydrogen peroxide. The produced hydroxyl radicals attack both the probe and the water-soluble antioxidants in 37 degrees C-incubated solutions for 2 h. The CUPRAC absorbance of the ethylacetate extract due to the reduction of Cu(II)-neocuproine reagent by the hydroxylated probe decreases in the presence of (.)OH scavengers, the difference being proportional to the scavenging ability of the tested compound. The developed method is less lengthy, more specific, and of a higher yield than the classical TBARS assay.

Immobilized Artificial Membrane HPLC Derived Parameters vs PAMPA-BBB Data in Estimating in Situ Measured Blood-Brain Barrier Permeation of Drugs.

PubMed

Grumetto, Lucia; Russo, Giacomo; Barbato, Francesco

2016-08-01

The affinity indexes for phospholipids (log kW(IAM)) for 42 compounds were measured by high performance liquid chromatography (HPLC) on two different phospholipid-based stationary phases (immobilized artificial membrane, IAM), i.e., IAM.PC.MG and IAM.PC.DD2. The polar/electrostatic interaction forces between analytes and membrane phospholipids (Δlog kW(IAM)) were calculated as the differences between the experimental values of log kW(IAM) and those expected for isolipophilic neutral compounds having polar surface area (PSA) = 0. The values of passage through a porcine brain lipid extract (PBLE) artificial membrane for 36 out of the 42 compounds considered, measured by the so-called PAMPA-BBB technique, were taken from the literature (P0(PAMPA-BBB)). The values of blood-brain barrier (BBB) passage measured in situ, P0(in situ), for 38 out of the 42 compounds considered, taken from the literature, represented the permeability of the neutral forms on "efflux minimized" rodent models. The present work was aimed at verifying the soundness of Δlog kW(IAM) at describing the potential of passage through the BBB as compared to data achieved by the PAMPA-BBB technique. In a first instance, the values of log P0(PAMPA-BBB) (32 data points) were found significantly related to the n-octanol lipophilicity values of the neutral forms (log P(N)) (r(2) = 0.782) whereas no significant relationship (r(2) = 0.246) was found with lipophilicity values of the mixtures of ionized and neutral forms existing at the experimental pH 7.4 (log D(7.4)) as well as with either log kW(IAM) or Δlog kW(IAM) values. log P0(PAMPA-BBB) related moderately to log P0(in situ) values (r(2) = 0.604). The latter did not relate with either n-octanol lipophilicity indexes (log P(N) and log D(7.4)) or phospholipid affinity indexes (log kW(IAM)). In contrast, significant inverse linear relationships were observed between log P0(in situ) (38 data points) and Δlog kW(IAM) values for all the compounds but ibuprofen and chlorpromazine, which behaved as moderate outliers (r(2) = 0.656 and r(2) = 0.757 for values achieved on IAM.PC.MG and IAM.PC.DD2, respectively). Since log P0(in situ) refer to the "intrinsic permeability" of the analytes regardless their ionization degree, no correction for ionization of Δlog kW(IAM) values was needed. Furthermore, log P0(in situ) were found roughly linearly related to log BB values (i.e., the logarithm of the ratio brain concentration/blood concentration measured in vivo) for all the analytes but those predominantly present at the experimental pH 7.4 as anions. These results suggest that, at least for the data set considered, Δlog kW(IAM) parameters are more effective than log P0(PAMPA-BBB) at predicting log P0(in situ) values for all the analytes. Furthermore, ionization appears to affect differently, and much more markedly, BBB passage of acids (yielding anions) than that of the other ionizable compounds.

Potentiometric Response Characteristics of Membrane-Based Cs + -Selective Electrodes Containing Ionophore-Functionalized Polymeric Microspheres

DOE PAGES

Peper, Shane; Gonczy, Chad

2011-01-01

Csmore » + -selective solvent polymeric membrane-based ion-selective electrodes (ISEs) were developed by doping ethylene glycol-functionalized cross-linked polystyrene microspheres (P-EG) into a plasticized poly(vinyl chloride) (PVC) matrix containing sodium tetrakis-(3,5-bis(trifluoromethyl)phenyl) borate (TFPB) as the ion exchanger. A systematic study examining the effects of the membrane plasticizers bis(2-ethylhexyl) sebacate (DOS), 2-nitrophenyl octyl ether (NPOE), and 2-fluorophenyl nitrophenyl ether (FPNPE) on the potentiometric response and selectivity of the corresponding electrodes was performed. Under certain conditions, P-EG-based ion-selective electrodes (ISEs) containing TFPB and plasticized with NPOE exhibited a super-Nernstian response between 1 × 10 − 3 and 1 × 10 − 4  M + , a response characteristic not observed in analogous membranes plasticized with either DOS or FPNPE. Additionally, the performance of P-EG-based ISEs was compared to electrodes based on two mobile ionophores, a neutral lipophilic ethylene glycol derivative (ethylene glycol monooctadecyl ether (U-EG)) and a charged metallacarborane ionophore, sodium bis(dicarbollyl)cobaltate(III) (CC). In general, P-EG-based electrodes plasticized with FPNPE yielded the best performance, with a linear range from 10 -1 –10 -5  M + , a conventional lower detection limit of 8.1 × 10 − 6  M + , and a response slope of 57.7 mV/decade. The pH response of P-EG ISEs containing TFPB was evaluated for membranes plasticized with either NPOE or FPNPE. In both cases, the electrodes remained stable throughout the pH range 3–12, with only slight proton interference observed below pH 3.« less

Phytosomal curcumin: A review of pharmacokinetic, experimental and clinical studies.

PubMed

Mirzaei, Hamed; Shakeri, Abolfazl; Rashidi, Bahman; Jalili, Amin; Banikazemi, Zarrin; Sahebkar, Amirhossein

2017-01-01

Curcumin, a hydrophobic polyphenol, is the principal constituent extracted from dried rhizomes of Curcuma longa L. (turmeric). Curcumin is known as a strong anti-oxidant and anti-inflammatory agent that has different pharmacological effects. In addition, several studies have demonstrated that curcumin is safe even at dosages as high as 8g per day; however, instability at physiological pH, low solubility in water and rapid metabolism results in a low oral bioavailability of curcumin. The phytosomal formulation of curcumin (a complex of curcumin with phosphatidylcholine) has been shown to improve curcumin bioavailability. Existence of phospholipids in phytosomes leads to specific physicochemical properties such as amphiphilic nature that allows dispersion in both hydrophilic and lipophilic media. The efficacy and safety of curcumin phytosomes have been shown against several human diseases including cancer, osteoarthritis, diabetic microangiopathy and retinopathy, and inflammatory diseases. This review focuses on the pharmacokinetics as well as pharmacological and clinical effects of phytosomal curcumin. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Solid-contact pH-selective electrode using multi-walled carbon nanotubes.

PubMed

Crespo, Gastón A; Gugsa, Derese; Macho, Santiago; Rius, F Xavier

2009-12-01

Multi-walled carbon nanotubes (MWCNT) are shown to be efficient transducers of the ionic-to-electronic current. This enables the development of a new solid-contact pH-selective electrode that is based on the deposition of a 35-microm thick layer of MWCNT between the acrylic ion-selective membrane and the glassy carbon rod used as the electrical conductor. The ion-selective membrane was prepared by incorporating tridodecylamine as the ionophore, potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate as the lipophilic additive in a polymerized methylmethacrylate and an n-butyl acrylate matrix. The potentiometric response shows Nernstian behaviour and a linear dynamic range between 2.89 and 9.90 pH values. The response time for this electrode was less than 10 s throughout the whole working range. The electrode shows a high selectivity towards interfering ions. Electrochemical impedance spectroscopy and chronopotentiometry techniques were used to characterise the electrochemical behaviour and the stability of the carbon-nanotube-based ion-selective electrodes.

Autonomous Rhythmic Drug Delivery Systems Based on Chemical and Biochemomechanical Oscillators

NASA Astrophysics Data System (ADS)

Siegel, Ronald A.

While many drug delivery systems target constant, or zero-order drug release, certain drugs and hormones must be delivered in rhythmic pulses in order to achieve their optimal effect. Here we describe studies with two model autonomous rhythmic delivery systems. The first system is driven by a pH oscillator that modulates the ionization state of a model drug, benzoic acid, which can permeate through a lipophilic membrane when the drug is uncharged. The second system is based on a nonlinear negative feedback instability that arises from coupling of swelling of a hydrogel membrane to an enzymatic reaction, with the hydrogel controlling access of substrate to the enzyme, and the enzyme's product controlling the hydrogel's swelling state. The latter system, whose autonomous oscillations are driven by glucose at constant external activity, is shown to deliver gonadotropin releasing hormone (GnRH) in rhythmic pulses, with periodicity of the same order as observed in sexually mature adult humans. Relevant experimental results and some mathematical models are reviewed.

Supramolecular Chemistry of Selective Anion Recognition for Anions of Environmental Relevance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bowman-James, Kristen

2004-12-01

This project have focuses on the basic chemical aspects of anion receptor design of functional pH independent systems, with the ultimate goal of targeting the selective binding of sulfate, as well as design of separations strategies for selective and efficient removal of targeted anions. Key findings include: (1) the first synthetic sulfate-selective anion-binding agents; (2) simple, structure-based methods for modifying the intrinsic anion selectivity of a given class of anion receptors; and (3) the first system capable of extracting sulfate anion from acidic, nitrate-containing aqueous media. Areas probed during the last funding period include: the design, synthesis, and physical andmore » structural characterization of receptors and investigation of anion and dual ion pair extraction using lipophilic amide receptors for anion binding. A new collaboration has been added to the project in addition to the one with Dr. Bruce Moyer at Oak Ridge National Laboratory, with Professor Jonathan Sessler at the University of Texas at Austin.« less

Development of an integrated electrochemical system for in vitro yeast viability testing.

PubMed

Adami, Andrea; Ress, Cristina; Collini, Cristian; Pedrotti, Severino; Lorenzelli, Leandro

2013-02-15

This work describes the development and testing of a microfabricated sensor for rapid cell growth monitoring, especially focused on yeast quality assessment for wine applications. The device consists of a NMOS ISFET sensor with Si(3)N(4) gate, able to indirectly monitor extracellular metabolism through pH variation of the medium, and a solid-state reference electrode implemented with PVC membranes doped with lipophilic salts (tetrabutylammonium-tetrabutylborate (TBA-TBB) and Potassium tetrakis(4-chlorphenyl)borate (KTClpB)). The use of a solid state reference electrode enables the implementation of a large number of cell assays in parallel, without the need of external conventional reference electrodes. Microbial growth testing has been performed both in standard culture conditions and on chip at different concentrations of ethanol in order to carry out a commonly used screening of wine yeast strains. Cell growth tests can be performed in few hours, providing a fast, sensitive and low cost analysis with respect to the conventional procedures. Copyright © 2012 Elsevier B.V. All rights reserved.

Quercetin solubilisation in bile salts: A comparison with sodium dodecyl sulphate.

PubMed

Buchweitz, Maria; Kroon, Paul A; Rich, Gillian T; Wilde, Peter J

2016-11-15

To understand the bioaccessibility of the flavonoid quercetin we studied its interaction with bile salt micelles. The environmental sensitivity of quercetin's UV-visible absorption spectrum gave information about quercetin partitioning. Two quercetin absorption peaks gave complementary information: Peak A (240-280nm) on the intermicellar phase and Peak B (340-440nm) on the micellar phase. Thus, by altering pH, we showed that only non-ionised quercetin partitions into micelles. We validated our interpretation by studying quercetin's interaction with SDS micelles. Pyrene fluorescence and the quercetin UV-visible spectra show that the adsorption site for pyrene and quercetin in bile salt micelles is more hydrophobic than that for SDS micelles. Also, both quercetin and pyrene reported a higher critical micelle concentration for bile salts than for SDS. Our method of using a flavonoid as an intrinsic probe, is generally applicable to other lipophilic bioactives, whenever they have observable environmental dependent properties. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Gelucire44/14 as a novel absorption enhancer for drugs with different hydrophilicities: in vitro and in vivo improvement on transcorneal permeation.

PubMed

Liu, Rui; Liu, Zhidong; Zhang, Chengui; Zhang, Boli

2011-08-01

The objective of this study was to investigate the application of Gelucire44/14 as a novel absorption enhancer in ophthalmic drug delivery system. Six compounds, namely ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin in the order of increasing lipophilicity were selected as model drugs. The effect of Gelucire44/14 on transcorneal permeation was evaluated across excised rabbit cornea. Ocular irritation and precorneal retention time were assessed. Additionally, aqueous humor pharmacokinetic test was performed by microdialysis. The results indicated that Gelucire44/14, at a concentration of 0.05% or 0.1% (w/v), was found to maximally increase the apparent permeability coefficient by 6.47-, 4.14-, 3.50-, 3.97-, 2.92-, and 1.86-fold for ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin, respectively (p < 0.05). Moreover, Gelucire44/14 was nonirritant at broad concentrations of 0.025%-0.4% (w/v). Pharmacokinetic tests showed that Gelucire44/14 promoted ocular bioavailability of the compounds as indicated by 5.40-, 4.03-, 3.46-, 3.57-, 2.77-, and 1.77-fold maximal increase in the area under the curve for the drugs aforementioned, respectively (p < 0.01). Therefore, Gelucire44/14 exerted a significant improvement on the permeation of both hydrophilic and lipophilic compounds, especially hydrophilic ones. Hence, Gelucire44/14 can be considered as a safe and effective absorption enhancer for ophthalmic drug delivery system. Copyright © 2011 Wiley-Liss, Inc.

Intelligent pH indicator film composed of agar/potato starch and anthocyanin extracts from purple sweet potato.

PubMed

Choi, Inyoung; Lee, Jun Young; Lacroix, Monique; Han, Jaejoon

2017-03-01

A new colorimetric pH indicator film was developed using agar, potato starch, and natural dyes extracted from purple sweet potato, Ipomoea batatas. Both agar and potato starch are solid matrices used to immobilize natural dyes, anthocyanins. The ultraviolet-visible (UV-vis) spectrum of anthocyanin extract solutions and agar/potato starch films with anthocyanins showed color variations to different pH values (pH 2.0-10.0). Fourier transform infrared (FT-IR) and UV-vis region spectra showed compatibility between agar, starch, and anthocyanin extracts. Color variations of pH indicator films were measured by a colorimeter after immersion in different pH buffers. An application test was conducted for potential use as a meat spoilage sensor. The pH indicator films showed pH changes and spoilage point of pork samples, changing from red to green. Therefore, the developed pH indicator films could be used as a diagnostic tool for the detection of food spoilage. Copyright © 2016 Elsevier Ltd. All rights reserved.

First biological evaluation of developed 3-benzyloxyfluorenes as novel class of MDR modulators.

PubMed

Krug, Martin; Voigt, Burkhardt; Baumert, Christiane; Lüpken, Ralf; Molnár, Joséf; Hilgeroth, Andreas

2010-06-01

A series of 3-benzyloxy-1-aza-9-oxafluorenes has been synthesized and biologically evaluated as novel MDR modulators. The concentration dependent inhibition of the efflux pump ABCB1 (P-glycoprotein) has been characterized and is discussed in relation to calculated lipophilicity data. Instead of the molecular lipophilicity the exact positioning of functional groups was found decisive for the biological activities. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Does lipophilicity of toxic compounds determine effects on drought tolerance of the soil collembolan Folsomia candida?

PubMed

Skovlund, Gitte; Damgaard, Christian; Bayley, Mark; Holmstrup, Martin

2006-12-01

The ability of Collembola to survive drought stress is crucial for their distribution in the terrestrial environment. Previous studies have suggested that several toxic compounds affect the drought tolerance of Folsomia candida in a synergistic manner and that these compounds have the feature in common that they elicit their toxicity by causing membrane damage. We hypothesised that the detrimental effect of toxic chemicals on drought tolerance in F. candida depends on the lipophilicity (log K(ow)) of the compound because a higher log K(ow) would mean a closer interaction with membranes. In this study the three chemicals 4-nonylphenol, pyrene and p,p'-DDE were tested. Surprisingly, 4-nonylphenol, with the lowest log K(ow), was the most potent with respect to reducing drought tolerance followed by pyrene, suggesting that interactions between drought tolerance and chemical stress do not depend on lipophilicity alone.

Lipophilicity Assessment of Ruthenium(II)-Arene Complexes by the Means of Reversed-Phase Thin-Layer Chromatography and DFT Calculations

PubMed Central

Shweshein, Khalil Salem A. M.; Andrić, Filip; Radoičić, Aleksandra; Gruden-Pavlović, Maja; Tešić, Živoslav; Milojković-Opsenica, Dušanka

2014-01-01

The lipophilicity of ten ruthenium(II)-arene complexes was assessed by reversed-phase thin-layer chromatography (RP-TLC) on octadecyl silica stationary phase. The binary solvent systems composed of water and acetonitrile were used as mobile phase in order to determine chromatographic descriptors for lipophilicity estimation. Octanol-water partition coefficient, logK OW, of tested complexes was experimentally determined using twenty-eight standard solutes which were analyzed under the same chromatographic conditions as target substances. In addition, ab initio density functional theory (DFT) computational approach was employed to calculate logK OW values from the differences in Gibbs' free solvation energies of the solute transfer from n-octanol to water. A good overall agreement between DFT calculated and experimentally determined logK OW values was established (R 2 = 0.8024–0.9658). PMID:24587761

The synthesis of amphipathic prodrugs of 1,2-diol drugs with saccharide conjugates by high regioselective enzymatic protocol.

PubMed

Quan, Jing; Chen, Zhichun; Han, Chengyou; Lin, Xianfu

2007-02-15

A facile, high regioselective enzymatic synthesis approach for the preparation of amphipathic prodrugs with saccharides of mephenesin and chlorphenesin was developed. Firstly, transesterification of two drugs with divinyl dicarboxylates with different carbon chain length was performed under the catalysis of Candida antarctica lipase acrylic resin and Lipozyme in anhydrous acetone at 50 degrees C, respectively. A series of lipophilic derivatives with vinyl groups of mephenesin and chlorphenesin were prepared. The influences of different organic solvents, enzyme sources, reaction time, and the acylation reagents on the synthesis of vinyl esters were investigated. And then, protease-catalyzed high regioselective acylation of D-glucose and D-mannose with vinyl esters of mephenesin and chlorphenesin gave drug-saccharide derivatives in good yields. The studies of lipophilicity and hydrolysis in vitro of prodrugs verified that drug-saccharide derivatives had amphipathic properties, and both lipophilic and amphipathic drug derivatives had obvious controlled release characteristics.

First Detection of Tetrodotoxin in Greek Shellfish by UPLC-MS/MS Potentially Linked to the Presence of the Dinoflagellate Prorocentrum minimum

PubMed Central

Vlamis, Aristidis; Katikou, Panagiota; Rodriguez, Ines; Rey, Verónica; Alfonso, Amparo; Papazachariou, Angelos; Zacharaki, Thetis; Botana, Ana M.; Botana, Luis M.

2015-01-01

During official shellfish control for the presence of marine biotoxins in Greece in year 2012, a series of unexplained positive mouse bioassays (MBA) for lipophilic toxins with nervous symptomatology prior to mice death was observed in mussels from Vistonikos Bay–Lagos, Rodopi. This atypical toxicity coincided with (a) absence or low levels of regulated and some non-regulated toxins in mussels and (b) the simultaneous presence of the potentially toxic microalgal species Prorocentrum minimum at levels up to 1.89 × 103 cells/L in the area’s seawater. Further analyses by different MBA protocols indicated that the unknown toxin was hydrophilic, whereas UPLC-MS/MS analyses revealed the presence of tetrodotoxins (TTXs) at levels up to 222.9 μg/kg. Reviewing of official control data from previous years (2006–2012) identified a number of sample cases with atypical positive to asymptomatic negative MBAs for lipophilic toxins in different Greek production areas, coinciding with periods of P. minimum blooms. UPLC-MS/MS analysis of retained sub-samples from these cases revealed that TTXs were already present in Greek shellfish since 2006, in concentrations ranging between 61.0 and 194.7 μg/kg. To our knowledge, this is the earliest reported detection of TTXs in European bivalve shellfish, while it is also the first work to indicate a possible link between presence of the toxic dinoflagellate P. minimum in seawater and that of TTXs in bivalves. Confirmed presence of TTX, a very heat-stable toxin, in filter-feeding mollusks of the Mediterranean Sea, even at lower levels to those inducing symptomatology to humans, indicates that this emerging risk should be seriously taken into account by the EU to protect the health of shellfish consumers. PMID:26008234

Development of an extended-range fiber optic pH sensor using evanescent wave absorption of sol-gel-entrapped pH indicators

NASA Astrophysics Data System (ADS)

Butler, Thomas M.; MacCraith, Brian D.; McDonagh, Colette M.

1995-09-01

The sol-gel process has been used to entrap pH indicators in porous glass coatings for sensor applications. This sensor is based on evanescent wave absorption using an unclad optical fiber dipcoated with the pH sensitive coating. The entrapped pH indicators show a broadening of the pH range with respect to the behavior in solution giving accurate measurement over three pH units when one indicator is used (bromophenol blue) and over six pH units (pH 3-9) when two indicators are used (bromophenol blue and bromocresol purple). The response of the pH sensor was monitored by measuring absorption at 590 nm referenced against a nonabsorbing region of the spectrum. This enabled the use of LED sources together with low cost photodiodes. The sensor displayed short response time and good repeatability. The thickness and stability of the pH sensitive coatings can be influenced by modifying the composition of the starting sol mixture. The evanescent absorption, and hence the sensitivity of the sensor, can be increased by selectively launching higher order modes in the fiber. These issues together with a full sensor characterization will be reported.

A new SOD mimic, Mn(III) ortho N-butoxyethylpyridylporphyrin combines superb potency and lipophilicity with low toxicity

PubMed Central

Rajic, Zrinka; Tovmasyan, Artak; Spasojevic, Ivan; Sheng, Huaxin; Lu, Miaomiao; Li, Alice M.; Gralla, Edith B.; Warner, David S.; Benov, Ludmil; Batinic-Haberle, Ines

2012-01-01

The Mn porphyrins of kcat(O2˙−) as high as that of a superoxide dismutase enzyme, and of optimized lipophilicity have already been synthesized. Their exceptional in vivo potency is at least in part due to their ability to mimic site and location of mitochondrial superoxide dismutase, MnSOD. MnTnHex-2-PyP5+ is the most studied among lipophilic Mn porphyrins. It is of remarkable efficacy in animal models of oxidative stress injuries and particularly in central nervous system diseases. However, when used at high single and multiple doses it becomes toxic. The toxicity of MnTnHex-2-PyP5+ has been in part attributed to its micellar properties, i.e. the presence of polar cationic nitrogens and hydrophobic alkyl chains. The replacement of a CH2 group by oxygen atom in each of the four alkyl chains was meant to disrupt the porphyrin micellar character. When such modification occurs at the end of long alkyl chains, the oxygens become heavily solvated, which leads to a significant drop in the lipophilicity of porphyrin. However, when the oxygen atoms are buried deeper within the long heptyl chains, their excessive solvation is precluded and the lipophilicity preserved. The presence of oxygens and the high lipophilicity bestow the exceptional chemical and physical properties to Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP5+. The high SOD-like activity is fully preserved and somewhat enhanced: log kcat(O2˙−) = 7.83 vs 7.48 and 7.65 for MnTnHex-2-PyP5+ and MnTnHep-2-PyP5+, respectively. MnTnBuOE-2-PyP5+ was tested in an O2˙− - specific in vivo assay – aerobic growth of SOD-deficient yeast, Saccharomyces cerevisiae, where it was fully protective in the range of 5 – 30 µM. MnTnHep-2-PyP5+ was already toxic at 5 µM, and MnTnHex-2-PyP5+ became toxic at 30 µM. In a mouse toxicity study, MnTnBuOE-2-PyP5+ was several-fold less toxic than either MnTnHex-2-PyP5+ or MnTnHep-2-PyP5+. PMID:22336516

Heterogeneous transport of digitalis-like compounds by P-glycoprotein in vesicular and cellular assays.

PubMed

Gozalpour, Elnaz; Wilmer, Martijn J; Bilos, Albert; Masereeuw, Rosalinde; Russel, Frans G M; Koenderink, Jan B

2016-04-01

Digitalis-like compounds (DLCs), the ancient medication of heart failure and Na,K-ATPase inhibitors, are characterized by their toxicity. Drug-drug interactions (DDIs) at absorption and excretion levels play a key role in their toxicity, hence, knowledge about the transporters involved might prevent these unwanted interactions. In the present study, the transport of fourteen DLCs with human P-glycoprotein (P-gp; ABCB1) was studied using a liquid chromatography-mass spectrometry (LC-MS) quantification method. DLC transport by P-gp overexpressing Madin-Darby canine kidney (MDCK) and immortalized human renal cells (ciPTEC) was compared to vesicular DLC transport. Previously, we identified convallatoxin as a substrate using membrane vesicles overexpressing P-gp; however, we could not measure transport of other DLCs in this assay (Gozalpour et al., 2014a). Here, we showed that lipophilic digitoxin, digoxigenin, strophanthidin and proscillaridin A are P-gp substrates in cellular accumulation assays, whereas the less lipophilic convallatoxin was not. P-gp function in the cellular accumulation assays depends on the entrance of lipophilic compounds by passive diffusion, whereas the vesicular transport assay is more appropriate for hydrophilic substrates. In conclusion, we identified digitoxin, digoxigenin, strophanthidin and proscillaridin A as P-gp substrates using cellular accumulation assays and recognized lipophilicity as an important factor in selecting a suitable transport assay. Copyright © 2016 Elsevier B.V. All rights reserved.

Lipophilic Fraction of Cultivated Bifurcaria bifurcata R. Ross: Detailed Composition and In Vitro Prospection of Current Challenging Bioactive Properties.

PubMed

Santos, Sónia A O; Trindade, Stephanie S; Oliveira, Catia S D; Parreira, Paula; Rosa, Daniela; Duarte, Maria F; Ferreira, Isabel; Cruz, Maria T; Rego, Andreia M; Abreu, Maria H; Rocha, Silvia M; Silvestre, Armando J D

2017-11-01

Macroalgae have been seen as an alternative source of molecules with promising bioactivities to use in the prevention and treatment of current lifestyle diseases. In this vein, the lipophilic fraction of short-term (three weeks) cultivated Bifurcaria bifurcata was characterized in detail by gas chromatography-mass spectrometry (GC-MS). B. bifurcata dichloromethane extract was composed mainly by diterpenes (1892.78 ± 133.97 mg kg -1 dry weight (DW)), followed by fatty acids, both saturated (550.35 ± 15.67 mg kg -1 DW) and unsaturated (397.06 ± 18.44 mg kg -1 DW). Considerable amounts of sterols, namely fucosterol (317.68 ± 26.11 mg kg -1 DW) were also found. In vitro tests demonstrated that the B. bifurcata lipophilic extract show antioxidant, anti-inflammatory and antibacterial activities (against both Gram-positive and Gram-negative bacteria), using low extract concentrations (in the order of µg mL -1 ). Enhancement of antibiotic activity of drug families of major clinical importance was observed by the use of B. bifurcata extract. This enhancement of antibiotic activity depends on the microbial strain and on the antibiotic. This work represents the first detailed phytochemical study of the lipophilic extract of B. bifurcata and is, therefore, an important contribution for the valorization of B. bifurcata macroalgae, with promising applications in functional foods, nutraceutical, cosmetic and biomedical fields.

Clathrin to Lipid Raft-Endocytosis via Controlled Surface Chemistry and Efficient Perinuclear Targeting of Nanoparticle.

PubMed

Chakraborty, Atanu; Jana, Nikhil R

2015-09-17

Nanoparticle interacts with live cells depending on their surface chemistry, enters into cell via endocytosis, and is commonly trafficked to an endosome/lysozome that restricts subcellular targeting options. Here we show that nanoparticle surface chemistry can be tuned to alter their cell uptake mechanism and subcellular trafficking. Quantum dot based nanoprobes of 20-30 nm hydrodynamic diameters have been synthesized with tunable surface charge (between +15 mV to -25 mV) and lipophilicity to influence their cellular uptake processes and subcellular trafficking. It is observed that cationic nanoprobe electrostatically interacts with cell membrane and enters into cell via clathrin-mediated endocytosis. At lower surface charge (between +10 mV to -10 mV), the electrostatic interaction with cell membrane becomes weaker, and additional lipid raft endocytosis is initiated. If a lipophilic functional group is introduced on a weakly anionic nanoparticle surface, the uptake mechanism shifts to predominant lipid raft-mediated endocytosis. In particular, the zwitterionic-lipophilic nanoprobe has the unique advantage as it weakly interacts with anionic cell membrane, migrates toward lipid rafts for interaction through lipophilic functional group, and induces lipid raft-mediated endocytosis. While predominate or partial clathrin-mediated entry traffics most of the nanoprobes to lysozome, predominate lipid raft-mediated entry traffics them to perinuclear region, particularly to the Golgi apparatus. This finding would guide in designing appropriate nanoprobe for subcellular targeting and delivery.

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity

PubMed Central

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M.

2016-01-01

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (SC) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. The ease and efficiency of double-click helix stabilization chemistries is a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control SC absorption and clearance rates to customize plasma pharmacokinetics. PMID:27327034

Lipophilic stinging nettle extracts possess potent anti-inflammatory activity, are not cytotoxic and may be superior to traditional tinctures for treating inflammatory disorders

PubMed Central

Johnson, Tyler A.; Sohn, Johann; Inman, Wayne D.; Bjeldanes, Leonard F.; Rayburn, Keith

2012-01-01

Extracts of four plant portions (roots, stems, leaves and flowers) of Urtica dioica, (the stinging nettle) were prepared using accelerated solvent extraction (ASE) involving water, hexanes, methanol and dichloromethane. The extracts were evaluated for their anti-inflammatory and cytotoxic activity in an NF-κB luciferase and MTT assay using macrophage immune (RAW264.7) cells. A standardized commercial ethanol extract of nettle leaves were also evaluated. The methanolic extract of the flowering portions displayed significant anti-inflammatory activity on par with the standard anti-inflammatory agent celastrol (1) but was moderately cytotoxic. Alternatively, the polar extracts (water, methanol, ethanol) of the roots, stems and leaves plant portions displayed moderate to weak anti-inflammatory activity, while the methanol and especially the water soluble extracts exhibited noticeable cytotoxicity. In contrast, the lipophilic dichloromethane extracts of the roots, stems and leaves exhibited potent anti-inflammatory effects ≥ 1 with minimal cytotoxicity to RAW264.7 cells. Collectively these results suggest that using lipophilic extracts of the roots, stems or leaves of stinging nettle may be more effective then traditional tinctures (water, methanol, ethanol) to undergo clinical evaluations for the treatment of inflammatory disorders including arthritis. A chemical investigation into the lipophillic extracts of stinging nettle to identify the bioactive compound(s) responsible for their observed anti-inflammatory activity is further warranted. PMID:23092723

Lipophilic stinging nettle extracts possess potent anti-inflammatory activity, are not cytotoxic and may be superior to traditional tinctures for treating inflammatory disorders.

PubMed

Johnson, Tyler A; Sohn, Johann; Inman, Wayne D; Bjeldanes, Leonard F; Rayburn, Keith

2013-01-15

Extracts of four plant portions (roots, stems, leaves and flowers) of Urtica dioica (the stinging nettle) were prepared using accelerated solvent extraction (ASE) involving water, hexanes, methanol and dichloromethane. The extracts were evaluated for their anti-inflammatory and cytotoxic activities in an NF-κB luciferase and MTT assay using macrophage immune (RAW264.7) cells. A standardized commercial ethanol extract of nettle leaves was also evaluated. The methanolic extract of the flowering portions displayed significant anti-inflammatory activity on par with a standard compound celastrol (1) but were moderately cytotoxic. Alternatively, the polar extracts (water, methanol, ethanol) of the roots, stems and leaves displayed moderate to weak anti-inflammatory activity, while the methanol and especially the water soluble extracts exhibited noticeable cytotoxicity. In contrast, the lipophilic dichloromethane extracts of the roots, stems and leaves exhibited potent anti-inflammatory effects greater than or equal to 1 with minimal cytotoxicity to RAW264.7 cells. Collectively these results suggest that using lipophilic extracts of stinging nettle may be more effective than traditional tinctures (water, methanol, ethanol) in clinical evaluations for the treatment of inflammatory disorders especially arthritis. A chemical investigation into the lipophilic extracts of stinging nettle to identify the bioactive compound(s) responsible for their observed anti-inflammatory activity is further warranted. Published by Elsevier GmbH.

Comparison Study of Two Differently Clicked 18F-Folates—Lipophilicity Plays a Key Role

PubMed Central

Kettenbach, Kathrin; Reffert, Laura M.; Schieferstein, Hanno; Pektor, Stefanie; Eckert, Raphael; Miederer, Matthias; Rösch, Frank

2018-01-01

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked 18F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with 18F-DBCO-folate, 18F-Ala-folate (logD = −1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, 18F-Ala-folate is expected to be a promising candidate for FR-PET imaging. PMID:29562610

Comprehensive analysis of the lipophilic reactive carbonyls present in biological specimens by LC/ESI-MS/MS.

PubMed

Tomono, Susumu; Miyoshi, Noriyuki; Ohshima, Hiroshi

2015-04-15

A new analytical method has been developed for profiling lipophilic reactive carbonyls (RCs) such as aldehydes and ketones in biological samples using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) with selected reaction monitoring (SRM). The method consists of several phases, including (1) extraction of lipophilic RCs with a chloroform/methanol mixture; (2) derivatization of the extracted RCs with dansyl hydrazine (DH); and (3) SRM detection of the characteristic product ion of the 5-dimethylaminonaphthalene-1-sulfonyl moiety (m/z 236.1). The analytical results were expressed as RC maps, which allowed for the occurrence and levels of different lipophilic RCs to be visualized. We also developed a highly reproducible and accurate method to extract, purify and derivatize RCs in small volumes of biological specimens. This method was applied to the detection of free RCs in mice plasma samples, and resulted in the detection of more than 400 RCs in samples obtained from C57BL/6J mice. Thirty-four of these RCs were identified by comparison with authentic RCs. This method could be used to investigate the levels of RCs in biological and environmental samples, as well as studying the role of lipid peroxidation in oxidative stress related-disorders and discovering new biomarkers for the early diagnosis of these diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

In vitro and in vivo evaluation of 11C-SD5024, a novel PET radioligand for human brain imaging of cannabinoid CB1 receptors

PubMed Central

Tsujikawa, Tetsuya; Zoghbi, Sami S.; Hong, Jinsoo; Donohue, Sean R.; Jenko, Kimberly J.; Gladding, Robert L.; Halldin, Christer; Pike, Victor W.; Innis, Robert B.; Fujita, Masahiro

2013-01-01

We recently developed a novel cannabinoid subtype-1 (CB1) receptor radioligand 11C-SD5024 for brain imaging. This study aimed to evaluate 11C-SD5024 both in vitro and in vivo and compare it with the other CB1 receptor ligands previously used in humans, i.e., 11C-MePPEP, 11C-OMAR, 18F-MK-9470, and 18F-FMPEP-d2. In vitro experiments were performed to measure dissociation constant (Ki) in human brain and to measure the lipophilicity of five CB1 receptor ligands listed above. In vivo specific binding in monkeys was measured by comparing total distribution volume (VT) at baseline and after full receptor blockade. The kinetics of 11C-SD5024 in humans were evaluated in seven healthy subjects with compartmental modeling. SD5024 showed Ki=0.47 nM, which was at an intermediate level among the five CB1 receptor ligands. Lipophilicity (LogD7.4) was 3.79, which is appropriate for brain imaging. Monkey scans showed high proportion of specific binding: ~80% of VT. In humans, 11C-SD5024 showed peak brain uptake of 1.5–3 standardized uptake value, which was slightly higher than those of 11C-OMAR and 18F-MK-9470. One-compartment model showed good fitting, consistent with the vast majority of brain uptake being specific binding found in the monkey. Regional VT values were consistent with known distribution of CB1 receptors. VT calculated from 80 and 120 min of scan data were strongly correlated (R2=0.97), indicating that 80 min provided adequate information for quantitation and that the influence of radiometabolites was low. Intersubject variability for VT of 11C-SD5024 was 22%, which was low among the five radioligands and indicated precise measurement. In conclusion, 11C-SD5024 has appropriate affinity and lipophilicity, high specific binding, moderate brain uptake, and provides good precision to measure the binding. The results suggest that 11C-SD5024 is slightly better than or equivalent to 11C-OMAR and that both are suitable for clinical studies, especially those that involve two scans in one day. PMID:24076222

Improved Poly (D,L-lactide) nanoparticles-based formulation for hair follicle targeting.

PubMed

Fernandes, B; Silva, R; Ribeiro, A; Matamá, T; Gomes, A C; Cavaco-Paulo, A M

2015-06-01

Hair follicles are widely recognized as the preferential target and site of accumulation for nanoparticles after topical application. This feature is of particular importance for hair cosmetics, having the potential to refine the treatment of several hair follicle-related disorders. The aim of this work was to improve the preparation of Poly (D,L-lactide) (PLA) nanoparticles for in vivo follicular target and drug delivery. Envisaging a future industrial scale-up of the process, nanoprecipitation method was used to prepare PLA nanoparticles: the effect of several processing parameters on their properties was examined and the yield of nanoparticles formation determined. Encapsulation efficiencies and in vitro release profiles of lipophilic and hydrophilic model compounds were also assessed. In vitro cytotoxicity and ex vivo penetration studies were performed on a reference skin cell line (NCTC2455, human skin keratinocytes) and porcine skin, respectively. Using acetone : ethanol (50 : 50, v/v) as the solvent phase, 0.6% (w/w) of Pluronic(®) F68 as a surfactant agent and agitation to mix the solvent and non-solvent phases, a monodispersed population of non-cytotoxic spherical nanoparticles of approximately 150 nm was obtained. The yield of nanoparticles for this formulation was roughly 90%. After encapsulation of model compounds, no significant changes were found in the properties of particles and the entrapment efficiencies were above 80%. The release kinetics of dyes from PLA nanoparticles indicate an anomalous transport mechanism (diffusion and polymer degradation) for Nile Red (lipophilic) and a Fickian diffusion of first order for fluorescein 5(6)-isothiocyanate (hydrophilic). Ex vivo skin penetration studies confirmed the presence of nanoparticles along the entire follicular ducts. The optimized method allows the preparation of ideal PLA nanoparticles-based formulations for hair follicle targeting. PLA nanoparticles can effectively transport and release lipophilic and hydrophilic compounds into the hair follicles, and the yields obtained are acceptable for industrial purposes. © 2014 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Effect of topically applied dexpanthenol on epidermal barrier function and stratum corneum hydration. Results of a human in vivo study.

PubMed

Gehring, W; Gloor, M

2000-07-01

In a randomized, double-blind, placebo-controlled study the effect of topical dexpanthenol (CAS 81-13-0) formulated in two different lipophilic vehicles on epidermal barrier function in vivo was carried out. Seven days' treatment with dexpanthenol improved stratum corneum hydration and reduced transepidermal water loss. Active treatment was statistically different from the vehicle control on both measures. Our results suggest that topical dexpanthenol formulated in either lipophilic vehicle stabilizes the skin barrier function.

One-Pot Isomerization–Cross Metathesis–Reduction (ICMR) Synthesis of Lipophilic Tetrapeptides

PubMed Central

2015-01-01

An efficient, versatile and rapid method toward homologue series of lipophilic tetrapeptide derivatives (herein, the opioid peptides H-TIPP-OH and H-DIPP-OH) is reported. High atom economy and a minimal number of synthetic steps resulted from a one-pot tandem isomerization-cross metathesis-reduction sequence (ICMR), applicable both in solution and solid phase methodology. The broadly applicable synthesis proceeds with short reaction times and simple work-up, as illustrated in this work for alkylated opioid tetrapeptides. PMID:24906051

K+-selective nanospheres: maximising response range and minimising response time.

PubMed

Ruedas-Rama, Maria Jose; Hall, Elizabeth A H

2006-12-01

Cross-linked K(+) ion-selective copolymer nanospheres have been prepared by free-radical photo-initiated polymerization of n-butyl acrylate (nBA) with hexanedioldiacrylate (HDDA). Nanospheres (<200 nm) containing H(+)-chromoionophore (ETH 5294) and lipophilic salt (KTClPB) for H(+)-sensors, or ETH 5294, a K(+)-selective ionophore (valinomycin) and anionic sites for K(+)-sensors were compared, and the effect of varying the normalised concentrations for beta (R(T)(-)/L(T)) and gamma (C(m)(T)/L(T)) was studied. Experimental data were fitted to theoretical curves for the dynamic response range, based on the effect of changes in the concentration of these lipophilic sensing components incorporated into the spheres, and conditions identified for maximising the response range. A complex valinomycin-K(+) formation constant, log K(IL) = 13.13 +/- 2.22, was obtained in the nBA matrix, and from the calibration curves the apparent acid-dissociation equilibrium constant (pK(a) = 12.92 +/- 0.03) was extracted for the H(+)-sensing system, and the equilibrium exchange constant (pK(exch) = 6.16 +/- 0.03, at pH 7) calculated for the K(+)-sensing nanospheres. A basis for establishing optimum performance was identified, whereby response range and response time were balanced with maximum fluorescence yield. Parameters for achieving nanospheres with a response time <5 minutes, covering 2-3 orders of magnitude change in activity were identified, demanding nanospheres with radius <300 nm and beta(crit) approximately 0.6. An RSD(%) approximately 3% was obtained in a study of the reproducibility of the response of the proposed nanospheres, and selectivity was also evaluated for a K(+)-selective nanosensor using several cations as interfering agents. In most cases, the fluorescent emission spectra showed no response to the cations tested, confirming the selectivity of nanospheres to potassium ion. The nanosensors were satisfactorily applied to the determination of K(+) in samples mimicking physiological conditions.

Excipient foods: designing food matrices that improve the oral bioavailability of pharmaceuticals and nutraceuticals.

PubMed

McClements, David Julian; Xiao, Hang

2014-07-25

The oral bioavailability of many lipophilic bioactive agents (pharmaceuticals and nutraceuticals) is limited due to various physicochemical and physiological processes: poor release from food or drug matrices; low solubility in gastrointestinal fluids; metabolism or chemical transformation within the gastrointestinal tract; low epithelium cell permeability. The bioavailability of these agents can be improved by specifically designing food matrices that control their release, solubilization, transport, metabolism, and absorption within the gastrointestinal tract. This article discusses the impact of food composition and structure on oral bioavailability, and how this knowledge can be used to design excipient foods for improving the oral bioavailability of lipophilic bioactives. Excipient foods contain ingredients or structures that may have no bioactivity themselves, but that are able to promote the bioactivity of co-ingested bioactives. These bioactives may be lipophilic drugs in pharmaceutical preparations (such as capsules, pills, or syrups) or nutraceuticals present within food matrices (such as natural or processed foods and beverages).

Lipophilic extracts of Cynara cardunculus L. var. altilis (DC): a source of valuable bioactive terpenic compounds.

PubMed

Ramos, Patrícia A B; Guerra, Ângela R; Guerreiro, Olinda; Freire, Carmen S R; Silva, Artur M S; Duarte, Maria F; Silvestre, Armando J D

2013-09-04

Lipophilic extracts of Cynara cardunculus L. var. altilis (DC) from the south of Portugal (Baixo Alentejo) were studied by gas chromatography-mass spectrometry. One sesquiterpene lactone, four pentacyclic triterpenes, and four sterols were reported for the first time as cultivated cardoon components, namely, deacylcynaropicrin, β- and α-amyrin, lupenyl and ψ-taraxasteryl acetates, stigmasterol, 24-methylenecholesterol, campesterol, and Δ(5)-avenasterol. In addition, other new compounds were identified: ten fatty acids, eight long-chain aliphatic alcohols, and six aromatic compounds. Four triterpenyl fatty acid esters were also detected. Sesquiterpene lactones and pentacyclic triterpenes were the major lipophilic families, representing respectively 2-46% and 10-89% of the detected compounds. Cynaropicrin was the most abundant sesquiterpene lactone, while taraxasteryl acetate was the main pentacyclic triterpene. Fatty acids and sterols, mainly hexadecanoic acid and β-sitosterol, were present at lower amounts (1-20% and 1-11% of the detected compounds). Long-chain aliphatic alcohols and aromatic compounds were detected at reduced abundances (1-6% of the detected compounds).

Design of a serotonin 4 receptor radiotracer with decreased lipophilicity for single photon emission computed tomography.

PubMed

Fresneau, Nathalie; Dumas, Noé; Tournier, Benjamin B; Fossey, Christine; Ballandonne, Céline; Lesnard, Aurélien; Millet, Philippe; Charnay, Yves; Cailly, Thomas; Bouillon, Jean-Philippe; Fabis, Frédéric

2015-04-13

With the aim to develop a suitable radiotracer for the brain imaging of the serotonin 4 receptor subtype (5-HT4R) using single photon emission computed tomography (SPECT), we synthesized and evaluated a library of di- and triazaphenanthridines with lipophilicity values which were in the range expected to favour brain penetration, and which demonstrated specific binding to the target of interest. Adding additional nitrogen atoms to previously described phenanthridine ligands exhibiting a high unspecific binding, we were able to design a radioiodinated compound [(125)I]14. This compound exhibited a binding affinity value of 0.094 nM toward human 5-HT4R and a high selectivity over other serotonin receptor subtypes (5-HTR). In vivo SPECT imaging studies and competition experiments demonstrated that the decreased lipophilicity (in comparison with our previously reported compounds 4 and 5) allowed a more specific labelling of the 5-HT4R brain-containing regions. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

New potentially active pyrazinamide derivatives synthesized under microwave conditions.

PubMed

Jandourek, Ondrej; Dolezal, Martin; Kunes, Jiri; Kubicek, Vladimir; Paterova, Pavla; Pesko, Matus; Buchta, Vladimir; Kralova, Katarina; Zitko, Jan

2014-07-03

A series of 18 N-alkyl substituted 3-aminopyrazine-2-carboxamides was prepared in this work according to previously experimentally set and proven conditions using microwave assisted synthesis methodology. This approach for the aminodehalogenation reaction was chosen due to higher yields and shorter reaction times compared to organic reactions with conventional heating. Antimycobacterial, antibacterial, antifungal and photosynthetic electron transport (PET) inhibiting in vitro activities of these compounds were investigated. Experiments for the determination of lipophilicity were also performed. Only a small number of substances with alicyclic side chain showed activity against fungi which was the same or higher than standards and the biological efficacy of the compounds increased with rising lipophilicity. Nine pyrazinamide derivatives also inhibited PET in spinach chloroplasts and the IC50 values of these compounds varied in the range from 14.3 to 1590.0 μmol/L. The inhibitory activity was connected not only with the lipophilicity, but also with the presence of secondary amine fragment bounded to the pyrazine ring. Structure-activity relationships are discussed as well.

Machine learning models for lipophilicity and their domain of applicability.

PubMed

Schroeter, Timon; Schwaighofer, Anton; Mika, Sebastian; Laak, Antonius Ter; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-01-01

Unfavorable lipophilicity and water solubility cause many drug failures; therefore these properties have to be taken into account early on in lead discovery. Commercial tools for predicting lipophilicity usually have been trained on small and neutral molecules, and are thus often unable to accurately predict in-house data. Using a modern Bayesian machine learning algorithm--a Gaussian process model--this study constructs a log D7 model based on 14,556 drug discovery compounds of Bayer Schering Pharma. Performance is compared with support vector machines, decision trees, ridge regression, and four commercial tools. In a blind test on 7013 new measurements from the last months (including compounds from new projects) 81% were predicted correctly within 1 log unit, compared to only 44% achieved by commercial software. Additional evaluations using public data are presented. We consider error bars for each method (model based error bars, ensemble based, and distance based approaches), and investigate how well they quantify the domain of applicability of each model.

A selective optical sensor based on [9]mercuracarborand-3, a new type of ionophore with a chloride complexing cavity

NASA Technical Reports Server (NTRS)

Badr, I. H.; Johnson, R. D.; Diaz, M.; Hawthorne, M. F.; Bachas, L. G.; Daunert, S. (Principal Investigator)

2000-01-01

A highly selective optical sensor for chloride, based on the multidentate Lewis acid ionophore [9]mercuracarborand-3, is described herein. This sensor is constructed by embedding the mercuracarborand ionophore, a suitable pH-sensitive lipophilic dye, and lipophilic cationic sites in a plasticized polymeric membrane. The multiple complementary interactions offered by the preorganized complexing cavity of [9]mercuracarborand-3 is shown to control the anion selectivity pattern of the optical film. The film exhibits a significantly enhanced selectivity for chloride over a variety of lipophilic anions such as perchlorate, nitrate, salicylate, and thiocyanate. Furthermore, the optical selectivity coefficients obtained for chloride over other biologically relevant anions are shown to meet the selectivity requirements for the determination of chloride in physiological fluids, unlike previously reported chloride optical sensors. In addition, the optical film responds to chloride reversibly over a wide dynamic range (16 microM-136 mM) with fast response and recovery times.

Root Uptake of Lipophilic Zinc−Rhamnolipid Complexes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stacey, Samuel P.; McLaughlin, Michael J.; Cakmak, Ismail

This study investigated the formation and plant uptake of lipophilic metal-rhamnolipid complexes. Monorhamnosyl and dirhamnosyl rhamnolipids formed lipophilic complexes with copper (Cu), manganese (Mn), and zinc (Zn). Rhamnolipids significantly increased Zn absorption by Brassica napus var. Pinnacle roots in {sup 65}Zn-spiked ice-cold solutions, compared with ZnSO{sub 4} alone. Therefore, rhamnolipid appeared to facilitate Zn absorption via a nonmetabolically mediated pathway. Synchrotron XRF and XAS showed that Zn was present in roots as Zn-phytate-like compounds when roots were treated with Zn-free solutions, ZnSO{sub 4}, or Zn-EDTA. With rhamnolipid application, Zn was predominantly found in roots as the Zn-rhamnolipid complex. When appliedmore » to a calcareous soil, rhamnolipids increased dry matter production and Zn concentrations in durum (Triticum durum L. cv. Balcali-2000) and bread wheat (Triticum aestivum L. cv. BDME-10) shoots. Rhamnolipids either increased total plant uptake of Zn from the soil or increased Zn translocation by reducing the prevalence of insoluble Zn-phytate-like compounds in roots.« less

Formulation and in vitro study of antibacterial vaginal suppositories.

PubMed

Regdon, G; Gombkötö, S; Regdon, G; Selmeczi, B

1994-12-01

Vaginal suppositories frequently used in gynaecological therapy were studied. Several antibacterial pharmacons are used for the topical treatment of vaginitis of various origins. In view of the fact that the liberation of the given active substance and the subsequent therapeutic effect may be improved or inhibited by the vehicle, our aim was to find the optimal suppository base for vaginal suppositories containing sulfadimidine, chloramphenicol and gentamicin sulfate by means of in vitro experiments. On the basis of breaking hardness, disintegration time and spreading properties the French Suppocire NA product, and compositions of macrogols with lower molecular weight proved to be the best lipophilic and hydrophilic bases, respectively. Among the lipophilic bases the in vitro drug liberation of Suppocire NA was significantly better (P < 0.05) than the other lipophilic bases. This vehicle is recommended for the topical treatment of vaginitis, as these suppositories have the further advantage that they can easily be produced on a magistral, galenical or industrial scale as well.

Relationship between the lipophilicity of gallic acid n-alquil esters' derivatives and both myeloperoxidase activity and HOCl scavenging.

PubMed

Rosso, Rober; Vieira, Tiago O; Leal, Paulo C; Nunes, Ricardo J; Yunes, Rosendo A; Creczynski-Pasa, Tânia B

2006-09-15

The gallic acid and several n-alkyl gallates, with the same number of hydroxyl substituents, varying only in the side carbonic chain length, with respective lipophilicity defined through the C log P, were studied. It evidenced the structure-activity relationship of the myeloperoxidase activity inhibition and the hypochlorous acid scavenger property, as well as its low toxicity in rat hepatic tissue. The gallates with C log P below 3.0 (compounds 2-7) were more active against the enzyme activity, what means that the addition of 1-6 carbons (C log P between 0.92 and 2.92) at the side chain increased approximately 50% the gallic acid effect. However, a relationship between the HOCl scavenging capability and the lipophilicity was not observed. With these results it is possible to suggest that the gallates protect the HOCl targets through two mechanisms: inhibiting its production by the enzyme and scavenging the reactive specie.

The effect of desolvation on the binding of inhibitors to HIV-1 protease and cyclin-dependent kinases: Causes of resistance.

PubMed

Fong, Clifford W

2016-08-01

Studies of the cyclin-dependent kinase inhibitors and HIV-1 protease inhibitors have confirmed that ligand-protein binding is dependent on desolvation effects. It has been found that a four parameter linear model incorporating desolvation energy, lipophilicity, dipole moment and molecular volume of the ligands is a good model to describe the binding between ligands and kinases or proteases. The resistance shown by MDR proteases to the anti-viral drugs is multi-faceted involving varying changes in desolvation, lipophilicity and dipole moment interaction compared to the non-resistant protease. Desolvation has been shown to be the dominant factor influencing the effect of inhibitors against the cyclin-dependent kinases, but lipophilicity and dipole moment are also significant factors. The model can differentiate between the inhibitory activity of CDK2/cycE, CDK1/cycB and CDK4/cycD enzymes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Plasticizer Effects in the PVC Membrane of the Dibasic Phosphate Selective Electrode

PubMed Central

Carey, Clifton

2016-01-01

The PVC membrane of an ion-selective electrode (ISE) sensitive to dibasic phosphate ions (HPO4-ISE) has not been optimized for maximum selectivity, sensitivity, and useable ISE lifetime and further work was necessary to improve its performance. Two areas of investigation are reported here: include the parameters for the lipophilicity of the plasticizer compound used and the amount of cyclic polyamine ionophore incorporated in the PVC membrane. Six candidate plasticizers with a range of lipophilicity were evaluated for their effect on the useable lifetime, sensitivity, and selectivity of the ISE against 13 different anions. Selectivity was determined by a modified fixed interferent method, sensitivity was determined without interferents, and the usable lifetime evaluated at the elapsed time where 50% of the HPO4-ISE failed (L50). The results show that choosing a plasticizer that has a lipophilicity similar to the ionophore's results in the best selectivity and sensitivity and the longest L50. PMID:27347487

In Vitro Lipophilic Antioxidant Capacity, Antidiabetic and Antibacterial Activity of Citrus Fruits Extracts from Aceh, Indonesia

PubMed Central

Ernawita; Wahyuono, Ruri Agung; Hesse, Jana; Hipler, Uta-Christina; Elsner, Peter; Böhm, Volker

2017-01-01

This study reports in vitro lipophilic antioxidant, inhibition of α-amylase and antibacterial activities of extracts of peel and pulp of citrus samples from Aceh, Indonesia. HPLC (high-performance liquid chromatography), phytochemical, and FTIR (fourier transform infrared) analysis detected carotenoids, flavonoids, phenolic acids and terpenoids, contributing to the biological potencies. Most peel and pulp extracts contained lutein and lower concentrations of zeaxanthin, α-carotene, β-carotene and β-cryptoxanthin. The extracts also contained flavanone glycosides (hesperidin, naringin and neohesperidin), flavonol (quercetin) and polymethoxylated flavones (sinensetin, tangeretin). L-TEAC (lipophilic trolox equivalent antioxidant capacity) test determined for peel extracts higher antioxidant capacity compared to pulp extracts. All extracts presented α-amylase inhibitory activity, pulp extracts showing stronger inhibitory activity compared to peel extracts. All extracts inhibited the growth of both gram (+) and gram (−) bacteria, with peel and pulp extracts of makin showing the strongest inhibitory activity. Therefore, local citrus species from Aceh are potential sources of beneficial compounds with possible health preventive effects. PMID:28165379

In Vitro Lipophilic Antioxidant Capacity, Antidiabetic and Antibacterial Activity of Citrus Fruits Extracts from Aceh, Indonesia.

PubMed

Ernawita; Wahyuono, Ruri Agung; Hesse, Jana; Hipler, Uta-Christina; Elsner, Peter; Böhm, Volker

2017-02-03

This study reports in vitro lipophilic antioxidant, inhibition of α-amylase and antibacterial activities of extracts of peel and pulp of citrus samples from Aceh, Indonesia. HPLC (high-performance liquid chromatography), phytochemical, and FTIR (fourier transform infrared) analysis detected carotenoids, flavonoids, phenolic acids and terpenoids, contributing to the biological potencies. Most peel and pulp extracts contained lutein and lower concentrations of zeaxanthin, α-carotene, β-carotene and β-cryptoxanthin. The extracts also contained flavanone glycosides (hesperidin, naringin and neohesperidin), flavonol (quercetin) and polymethoxylated flavones (sinensetin, tangeretin). L-TEAC (lipophilic trolox equivalent antioxidant capacity) test determined for peel extracts higher antioxidant capacity compared to pulp extracts. All extracts presented α-amylase inhibitory activity, pulp extracts showing stronger inhibitory activity compared to peel extracts. All extracts inhibited the growth of both gram (+) and gram (-) bacteria, with peel and pulp extracts of makin showing the strongest inhibitory activity. Therefore, local citrus species from Aceh are potential sources of beneficial compounds with possible health preventive effects.

Polymethacrylate Polymers with Appended Aluminum(III)-Tetraphenylporphyrins: Synthesis, Characterization and Evaluation as Macromolecular Ionophores for Electrochemical and Optical Fluoride Sensors

PubMed Central

Wang, Lin; Meyerhoff, Mark E.

2008-01-01

The synthesis and characterization of a novel polymethacylate polymer with covalently linked Al(III)-tetraphenylporphyrin (Al(III)-TPP) groups is reported. The new polymer is examined as a potential macromolecular ionophore for the preparation of polymeric membrane-based potentiometric and optical fluoride selective sensors. To prepare the polymer, an Al(III) porphyrin monomer modified with a methacrylate functionality is synthesized, allowing insertion into a polymethacrylate block copolymer (methyl methacrylate and decyl methacrylate) backbone. The resulting polymer can then be incorporated, along with appropriate additives, into conventional plasticized poly(vinyl chloride) films for testing electrochemical and optical fluoride response properties. The covalent attachment of the Al(III)-TPP ionophore to the copolymer matrix provides potentiometric sensors that exhibit significant selectivity for fluoride ion with extended lifetimes (compared to ion-selective membrane electrodes formulated with conventional free Al(III)-TPP structure). However, quite surprisingly, the attachment of the ionophore to the polymer does not eliminate the interaction of Al(III)-TPP structures to form dimeric species within the membrane phase in the presence of fluoride ion. Such interactions are confirmed by UV/visible spectroscopy of the blended polymeric films. Use of the new polymer-Al(III)-TPP conjugates to prepare optical fluoride sensors by co-incorporating a lipophilic pH indicator (4’,5’-dibromofluorescein octadecyl ester; ETH7075) is also examined and the resulting optical sensing films are shown to exhibit excellent selectivity for fluoride, with the potential for prolonged operational lifetime. PMID:18298973

Sorption of nonpolar aromatic contaminants by chlorosilane surface modified natural minerals.

PubMed

Huttenloch, P; Roehl, K E; Czurda, K

2001-11-01

The efficacy of the surface modification of natural diatomite and zeolite material by chlorosilanes is demonstrated. Chlorosilanes used were trimethylchlorosilane (TMSCI), tert-butyldimethylchlorosilane (TBDMSCI), dimethyloctadecylchlorosilane (DMODSCI), and diphenyldichlorosilane (DPDSCI) possessing different headgroups and chemical properties. Silanol groups of the diatomite and zeolite were modified by chemical reaction with the chlorosilanes resulting in a stable covalent attachment of the organosilanes to the mineral surface. The alteration of surface properties of the modified material was proved by measurements of water adsorption capacity, total organic carbon (TOC) content, and thermoanalytical data. The surface modified material showed great stability even when exposed to extremes in ionic strength, pH, and to pure organic solvents. Sorption of toluene, o-xylene, and naphthalene from water was greatly enhanced by the surface modification compared to the untreated materials which showed no measurable sorption of these compounds. The enhanced sorption was dependent on the organic carbon content as well as on chemical characteristics of the chlorosilanes used. Batch sorption experiments showed that the phenyl headgroups of DPDSCI have the best affinity for aromatic compounds. Removal from an aqueous solution of 10 mg/L of naphthalene, o-xylene, and toluene was 71%, 60%, and 30% for surface modified diatomite and 51%, 30%, and 16% for modified clinoptilolite, respectively. Sorption data were well described by the Freundlich isotherm equation, which indicated physical adsorption onto the lipophilic surface rather than partitioning into the surface organic phase. The chlorosilane modified materials have an apparent potential for application in environmental technologies such as permeable reactive barriers (PRB) or wastewater treatment.

Phloretin-induced changes of lipophilic ion transport across the plasma membrane of mammalian cells.

PubMed Central

Sukhorukov, V L; Kürschner, M; Dilsky, S; Lisec, T; Wagner, B; Schenk, W A; Benz, R; Zimmermann, U

2001-01-01

The adsorption of the hydrophobic anion [W(CO)(5)CN](-) to human lymphoid Jurkat cells gave rise to an additional anti-field peak in the rotational spectra of single cells, indicating that the cell membrane displayed a strong dielectric dispersion in the kilohertz to megahertz frequency range. The surface concentration of the adsorbed anion and its translocation rate constant between the two membrane boundaries could be evaluated from the rotation spectra of cells by applying the previously proposed mobile charge model. Similar single-cell electrorotation experiments were performed to examine the effect of phloretin, a dipolar molecule known to influence the dipole potential of membranes, on the transport of [W(CO)(5)CN](-) across the plasma membrane of mammalian cells. The adsorption of [W(CO)(5)CN](-) was significantly reduced by phloretin, which is in reasonable agreement with the known phloretin-induced effects on artificial and biological membranes. The IC(50) for the effect of phloretin on the transport parameters of the lipophilic ion was approximately 10 microM. The results of this study are consistent with the assumption that the binding of phloretin reduces the intrinsic dipole potential of the plasma membrane. The experimental approach developed here allows the quantification of intrinsic dipole potential changes within the plasma membrane of living cells. PMID:11463642

Structural and dipolar properties of the voltage-dependent pore former alamethicin in octanol/dioxane.

PubMed Central

Schwarz, G; Savko, P

1982-01-01

Dielectric constant and loss of the membrane-active peptide alamethicin in octanol/dioxane mixtures have been measured at frequencies between 5 kHz and 50 MHz. On the basis of a rotational mechanism of dipolar orientation, the observed dispersion provides information regarding size, shape, and dipole moment of the structural entities which the solute may assume in media of diverse lipophilicity. Particularly detailed results are obtained in a pure octanol solvent where an apparent molecular weight of alamethicin could be determined. It turns out that in this quite lipophilic medium most of the peptide material exists as a monomer particle that has approximate length and diameter of 35 and 13 A, respectively. It carries a dipole moment of approximately 75 Debye units (directed nearly parallel to the long axis). At our concentrations of a few milligrams per milliliters, appreciable formation of dimers by head-to-tail linkage is indicated. When the octanol content is reduced by adding greater amounts of dioxane, larger particles are encountered. This is accompanied by a decrease of the effective polarity. The inherent increase of hydrophilicity in the dioxane-enriched solvent apparently favors another monomer conformation that has a low dipole moment and easily aggregates to some kind of micelle. PMID:7115881

Optimised method to estimate octanol water distribution coefficient (logD) in a high throughput format.

PubMed

Low, Ying Wei Ivan; Blasco, Francesca; Vachaspati, Prakash

2016-09-20

Lipophilicity is one of the molecular properties assessed in early drug discovery. Direct measurement of the octanol-water distribution coefficient (logD) requires an analytical method with a large dynamic range or multistep dilutions, as the analyte's concentrations span across several orders of magnitude. In addition, water/buffer and octanol phases which have very different polarity could lead to matrix effects and affect the LC-MS response, leading to erroneous logD values. Most compound libraries use DMSO stocks as it greatly reduces the sample requirement but the presence of DMSO has been shown to underestimate the lipophilicity of the analyte. The present work describes the development of an optimised shake flask logD method using deepwell 96 well plate that addresses the issues related to matrix effects, DMSO concentration and incubation conditions and is also amenable to high throughput. Our results indicate that the equilibrium can be achieved within 30min by flipping the plate on its side while even 0.5% of DMSO is not tolerated in the assay. This study uses the matched matrix concept to minimise the errors in analysing the two phases namely buffer and octanol in LC-MS. Copyright © 2016 Elsevier B.V. All rights reserved.

Diverse Human Skin Fungal Communities in Children Converge in Adulthood.

PubMed

Jo, Jay-Hyun; Deming, Clay; Kennedy, Elizabeth A; Conlan, Sean; Polley, Eric C; Ng, Weng-Ian; Segre, Julia A; Kong, Heidi H

2016-12-01

Understanding the skin mycobiome (fungal communities) is important because both commensal and pathogenic fungi can drive cutaneous disease depending on host status and body sites, including the scalp, feet, and groin. Interestingly, age may also affect skin fungal infections as certain dermatophytoses (i.e., tinea capitis) are more frequent in children than adults. We previously described the skin mycobiomes in healthy adults, showing lipophilic fungi Malassezia predominate in most skin sites. Because children have less sebaceous skin before puberty, we compared the fungal communities of primary clinical samples from healthy children and adults, based on sequencing of a fungal phylogenetic marker. Although Malassezia predominated on the trunk, head, and arm skin of adults (age 18-39), children (age < 14) had more diverse fungal communities, for example, Eurotiomycetes, which includes common dermatophytes. Species-level classification showed that Malassezia globosa predominated in children. Collectively, our findings indicate that prepubertal skin is colonized by diverse fungi, whereas adult skin is predominantly obligatory lipophilic Malassezia, suggesting that fungal communities on skin profoundly shift during puberty. Mycobiome shifts during puberty are likely due to alterations in sebaceous gland activation and sebum composition. This study provides a foundational framework for studies investigating interactions between fungi, skin, and pediatric dermatophytosis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Accelerated Stability Testing of a Clobetasol Propionate-Loaded Nanoemulsion as per ICH Guidelines.

PubMed

Ali, Mohammad Sajid; Alam, Mohammad Sarfaraz; Alam, Nawazish; Anwer, Tarique; Safhi, Mohammed Mohsen A

2013-01-01

The physical and chemical degradation of drugs may result in altered therapeutic efficacy and even toxic effects. Therefore, the objective of this work was to study the stability of clobetasol propionate (CP) in a nanoemulsion. The nanoemulsion formulation containing CP was prepared by the spontaneous emulsification method. For the formulation of the nanoemulsion, Safsol, Tween 20, ethanol, and distilled water were used. The drug was incorporated into an oil phase in 0.05% w/v. The lipophilic nature of the drug led to the O/W nanoemulsion formulation. This was characterized by droplet size, pH, viscosity, conductivity, and refractive index. Stability studies were performed as per ICH guidelines for a period of three months. The shelf life of the nanoemulsion formulation was also determined after performing accelerated stability testing (40°C ± 2°C and 75% ± 5% RH). We also performed an intermediate stability study (30°C ± 2°C/65% RH ± 5% RH). It was found that the droplet size, conductivity, and refractive index were slightly increased, while the viscosity and pH slightly decreased at all storage conditions during the 3-month period. However, the changes in these parameters were not statistically significant (p≥0.05). The degradation (%) of the optimized nanoemulsion of CP was determined and the shelf life was found to be 2.18 years at room temperature. These studies confirmed that the physical and chemical stability of CP were enhanced in the nanoemulsion formulation.

Optode Membrane for Determination of Nicotine via Generation of Its Bromoethane Derivative.

PubMed

Choi, M M; Wu, X J; Li, Y R

1999-04-01

A plasticized poly(vinyl chloride) optode membrane incorporated with a valinomycin ionophore, a H(+)-selective chromoionophore (ETH 5294), and a lipophilic potassium tetrakis(4-chlorophenyl)borate was used as a reversible sensing device for the indirect optical determination of nicotine. Nicotine was extracted from a tobacco product (1-5 g) and converted to its bromoethane derivative (NBD(+)Br(-)) by reacting with a solution of bromoethane in ethanol. NBD(+)Br(-) in a solution of 0.05 M boric acid-Borax buffer and 0.2 mM Triton X-100 was extracted into the bulk of the membrane and subsequently caused changes in optical absorption of the sensing layer. The response slope, dynamic working range, detection limit, sensitivity, selectivity, effects of buffer solution and neutral surfactant Triton X-100, and lifetime were discussed in detail. The response was pH dependent. At pH 8.5, the detection range was extended from 0.4 μM to 1 mM. Typical response times (t(95)) of the samples were 2-4 min. The optode method was successfully used to detect nicotine in a tobacco sample from the market (average content 0.720%; RSD 0.044%; n = 11). The interference of K(+) on the optode method can be prevented by the pre-extraction procedure. Malic acid and citrate showed no interferences. The recovery of nicotine as NBD(+) was 84-119% in the range 0.035-5% nicotine. The result was satisfactory compared with an AOAC UV standard method.

Modified Folin-Ciocalteu antioxidant capacity assay for measuring lipophilic antioxidants.

PubMed

Berker, Kadriye Isil; Ozdemir Olgun, F Ayca; Ozyurt, Dilek; Demirata, Birsen; Apak, Resat

2013-05-22

The Folin-Ciocalteu (FC) method of performing a total phenolics assay, originally developed for protein determination, has recently evolved as a total antioxidant capacity assay but was found to be incapable of measuring lipophilic antioxidants due to the high affinity of the FC chromophore, that is, multivalent-charged phospho-tungsto-molybdate(V), toward water. Thus, the FC method was modified and standardized so as to enable simultaneous measurement of lipophilic and hydrophilic antioxidants in NaOH-added isobutanol-water medium. Optimal conditions were as follows: dilution ratio of aqueous FC reagent with iso-BuOH (1:2, v/v), final NaOH concentration of 3.5 × 10(-2) M, reaction time of 20 min, and maximum absorption wavelength of 665 nm. The modified procedure was successfully applied to the total antioxidant capacity assay of trolox, quercetin, ascorbic acid, gallic acid, catechin, caffeic acid, ferulic acid, rosmarinic acid, glutathione, and cysteine, as well as of lipophilic antioxidants such as α-tocopherol (vitamin E), butylated hydroxyanisole, butylated hydroxytoluene, tertiary butylhydroquinone, lauryl gallate, and β-carotene. The modified FC method reliably quantified ascorbic acid, whereas the conventional method could not. The modified method was reproducible and additive in terms of total antioxidant capacity values of constituents of complex mixtures such as olive oil extract and herbal tea infusion. The trolox equivalent antioxidant capacities of the tested antioxidant compounds correlated well with those found by the Cupric Reducing Antioxidant Capacity reference method.

Food matrix and processing influence on carotenoid bioaccessibility and lipophilic antioxidant activity of fruit juice-based beverages.

PubMed

Rodríguez-Roque, María Janeth; de Ancos, Begoña; Sánchez-Vega, Rogelio; Sánchez-Moreno, Concepción; Cano, M Pilar; Elez-Martínez, Pedro; Martín-Belloso, Olga

2016-01-01

The biological activity of carotenoids depends on their bioaccessibility and solubilization in the gastrointestinal tract. These compounds are poorly dispersed in the aqueous media of the digestive tract due to their lipophilic nature. Thus, it is important to analyze the extent to which some factors, such as the food matrix and food processing, may improve their bioaccessibility. Beverages formulated with a blend of fruit juices and water (WB), milk (MB) or soymilk (SB) were treated by high-intensity pulsed electric fields (HIPEF) (35 kV cm(-1) with 4 μs bipolar pulses at 200 Hz for 1800 μs), high-pressure processing (HPP) (400 MPa at 40 °C for 5 min) or thermal treatment (TT) (90 °C for 1 min) in order to evaluate the influence of food matrix and processing on the bioaccessibility of carotenoids and on the lipophilic antioxidant activity (LAA). The bioaccessibility of these compounds diminished after applying any treatment (HIPEF, HPP and TT), with the exception of cis-violaxanthin + neoxanthin, which increased by 79% in HIPEF and HPP beverages. The lowest carotenoid bioaccessibility was always obtained in TT beverages (losses up to 63%). MB was the best food matrix for improving the bioaccessibility of carotenoids, as well as the LAA. The results demonstrate that treatment and food matrix modulated the bioaccessibility of carotenoids as well as the lipophilic antioxidant potential of beverages. Additionally, HIPEF and HPP could be considered as promising technologies to obtain highly nutritional and functional beverages.

Transport of a series of D-phenylalanine-glycine hexapeptides across rat alveolar epithelia in vitro.

PubMed

Evans, J P; Tudball, N; Dickinson, P A; Farr, S J; Kellaway, I W

1998-01-01

The effect of lipophilicity on the absorption of peptides from the lungs was investigated. D-phenylalanine (F)-glycine (G) hexapeptides were synthesised to differ, predominantly, only in their lipophilicity. Rat alveolar type II cells were isolated and cultured on plastic, or polycarbonate filters; by day 6 they had de-differentiated to an alveolar type I-like epithelium. The permeability of the monolayers to the hexapeptides was determined. The hexapeptides were metabolically and chemically stable for greater than 24h in the presence of the cells. They did not adhere to the cell culture plastic and were associated only to a low extent with the cell monolayer. The apical to basolateral permeability coefficients for D-F1G5, D-F2G4, and D-F3G3 were 2.19+/-0.53, 1.75+/-0.42 and 2.20+/-0.56 x 10(-7) cm s(-1) respectively. The permeability of the monolayers to D-F1G5 and D-F2G4 was concentration and direction independent, however for D-F3G3 the monolayer was more permeable in the basolateral to apical direction. There was no correlation between the lipophilicity of the hexapeptides and permeability coefficients: other physicochemical parameters did not predict hexapeptide transport. Lipophilicity does not appear to control the transport of hexapeptides across the alveolar epithelium probably as a consequence of the peptides being transported via the paracellular route.

Factors determining accumulation of bisphenol A and alkylphenols at a low trophic level as exemplified by mussels Mytilus trossulus.

PubMed

Staniszewska, Marta; Graca, Bożena; Sokołowski, Adam; Nehring, Iga; Wasik, Andrzej; Jendzul, Anna

2017-01-01

The aim of the study was to investigate abiotic and biotic factors influencing the accumulation of endocrine disrupting compounds (EDCs) such as bisphenol A (BPA), 4-tert-octylphenol (OP) and 4-nonylphenol (NP) in mussels Mytilus trossulus from the Gulf of Gdansk (Southern Baltic). The key abiotic factor influencing BPA, OP and NP accumulation in mussels is their hydrophilicity/lipophilicity, which affects their main assimilation routes - by digestive tract for the more lipophilic OP and NP, and additionally by the gills for the less lipophilic BPA. As a result, high condition index (i.e. higher soft tissue weight) is more often correlated with high concentrations of OP and NP in mussels than with BPA. Furthermore, alkylphenols have 6-8 times greater accumulative potential than BPA. Concentration of the studied compounds was lower in females than in males following spawning, and the effect lasted longer for BPA than for alkylphenols. The influence of season and hydrological conditions on BPA, OP, NP in the mussel was more pronounced than the proximity of external sources of these compounds. An increase in water temperature in summer probably stimulated the solubility of BPA, the least lipophilic of the studied compounds, and led to increased assimilation of this compound from water (through gills). On the other hand, high OP and NP concentrations in mussels occurred in spring, which was caused by increased surface run-off and sediments resuspension. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of polyoxyethylene sorbitan esters and sodium caseinate on physicochemical properties of palm-based functional lipid nanodispersions.

PubMed

Cheong, Jean Ne; Mirhosseini, Hamed; Tan, Chin Ping

2010-06-01

The main objective of the present study was to investigate the effect of polyoxyethylene sorbitan esters and sodium caseinate on physicochemical properties of palm-based functional lipid nanodispersions prepared by the emulsification-evaporation technique. The results indicated that the average droplet size increased significantly (P < 0.05) by increasing the chain length of fatty acids and also by increasing the hydrophile-lipophile balance value. Among the prepared nanodispersions, the nanoemulsion containing Polysorbate 20 showed the smallest average droplet size (202 nm) and narrowest size distribution for tocopherol-tocotrienol nanodispersions, while sodium caseinate-stabilized nanodispersions containing carotenoids had the largest average droplet size (386 nm), thus indicating a greater emulsifying role for Polysorbate 20 compared with sodium caseinate.

Optimizing solubility and permeability of a biopharmaceutics classification system (BCS) class 4 antibiotic drug using lipophilic fragments disturbing the crystal lattice.

PubMed

Tehler, Ulrika; Fagerberg, Jonas H; Svensson, Richard; Larhed, Mats; Artursson, Per; Bergström, Christel A S

2013-03-28

Esterification was used to simultaneously increase solubility and permeability of ciprofloxacin, a biopharmaceutics classification system (BCS) class 4 drug (low solubility/low permeability) with solid-state limited solubility. Molecular flexibility was increased to disturb the crystal lattice, lower the melting point, and thereby improve the solubility, whereas lipophilicity was increased to enhance the intestinal permeability. These structural changes resulted in BCS class 1 analogues (high solubility/high permeability) emphasizing that simple medicinal chemistry may improve both these properties.

Novel self-powered pH indicator using ionic polymeric gel muscles

NASA Astrophysics Data System (ADS)

Shahinpoor, Mohsen

1994-05-01

A novel design for a torsional spring-loaded pH indicator using ionic polymeric gel fibrous muscles is presented. The essential parts of the proposed self-powered pH indicator are a pair of co-axial and concentric cylinders, an assembly of fibrous polyacrylonitrile (PAN) muscles, a torsional spring, and a dial indicator. The two co-axial cylinders are such that the inner cylinder may pivotally rotate about the central rotation axis that is fixed to the inner bottom or side of the outer cylinder. The outer cylinder also serves as a reservoir for any liquid whose pH is to be determined either statically or dynamically. The internal cylindrical drum is further equipped with a dial indicator on one of its outer end caps such that when a pH environment is present the contraction or expansion of the PAN fibers cause the inner drum to rotate and thus give a reading of the dial indicator. The motion of the dial indicator may also be converted to an electrical signal (voltage) for digital electronics display and computer control. A mathematical model is also presented for the dynamic response of the self-powered pH indicator made with contractile PAN fiber bundle assemblies.

Chronic systemic pesticide exposure reproduces features of Parkinson's disease.

PubMed

Betarbet, R; Sherer, T B; MacKenzie, G; Garcia-Osuna, M; Panov, A V; Greenamyre, J T

2000-12-01

The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.

Measurements of spectral responses for developing fiber-optic pH sensor

NASA Astrophysics Data System (ADS)

Yoo, Wook Jae; Heo, Ji Yeon; Jang, Kyoung Won; Seo, Jeong Ki; Moon, Jin Soo; Park, Jang-Yeon; Park, Byung Gi; Cho, Seunghyun; Lee, Bongsoo

2011-01-01

In this study, we have fabricated a fiber-optic pH sensor, which is composed of a light source, a pH-sensing probe, plastic optical fibers and a spectrometer, for determining the degree of infection by Helicobacter pylori in the stomach. As pH indicators, phenol red and m-cresol purple are used, and pH liquid solutions are prepared by mixing phenol red or m-cresol purple solutions and various kinds of pH buffer solutions. The light emitted by a light source is guided by plastic optical fibers to the pH liquid solution, and the optical characteristic of a reflected light is changed according to the color variations of the pH indicator in the pH-sensing probe. Therefore, we have measured the intensities and wavelength shifts of the reflected lights, which change according to the color variations of indicators at different pH values, by using a spectrometer for spectral analysis. Also, the relationships between the pH values of liquid solutions and the optical properties of the modulated lights are obtained on the basis of the changes of the colors of indicators.

A wearable fingernail chemical sensing platform: pH sensing at your fingertips.

PubMed

Kim, Jayoung; Cho, Thomas N; Valdés-Ramírez, Gabriela; Wang, Joseph

2016-04-01

This article demonstrates an example of a wearable chemical sensor based on a fingernail platform. Fingernails represent an attractive wearable platform, merging beauty products with chemical sensing, to enable monitoring of our surrounding environment. The new colorimetric pH fingernail sensor relies on coating artificial nails with a recognition layer consisted of pH indicators entrapped in a polyvinyl chloride (PVC) matrix. Such color changing fingernails offer fast and reversible response to pH changes, repeated use, and intense color change detected easily with naked eye. The PVC matrix prevents leaching out of the indicator molecules from the fingernail sensor toward such repeated use. The limited narrow working pH range of a single pH indicator has been addressed by multiplexing three different pH indicators: bromothymol blue (pH 6.0-7.6), bromocresol green (pH 3.8-5.4), and cresol red (pH 7.2-8.8), as demonstrated for analyses of real-life samples of acidic, neutral, and basic character. The new concept of an optical wearable chemical sensor on fingernail platforms can be expanded towards diverse analytes for various applications in connection to the judicious design of the recognition layer. Copyright © 2016 Elsevier B.V. All rights reserved.

Coencapsulation of (-)-Epigallocatechin-3-gallate and Quercetin in Particle-Stabilized W/O/W Emulsion Gels: Controlled Release and Bioaccessibility.

PubMed

Chen, Xing; McClements, David Julian; Wang, Jian; Zou, Liqiang; Deng, Sumeng; Liu, Wei; Yan, Chi; Zhu, Yuqing; Cheng, Ce; Liu, Chengmei

2018-04-11

Particle-stabilized W 1 /O/W 2 emulsion gels were fabricated using a two-step procedure: ( i) a W 1 /O emulsion was formed containing saccharose (for osmotic stress balance) and gelatin (as a gelling agent) in the aqueous phase and polyglycerol polyricinoleate (a lipophilic surfactant) in the oil phase; ( ii) this W 1 /O emulsion was then homogenized with another water phase (W 2 ) containing wheat gliadin nanoparticles (hydrophilic emulsifier). The gliadin nanoparticles in the external aqueous phase aggregated at pH 5.5, which led to the formation of particle-stabilized W 1 /O/W 2 emulsion gels with good stability to phase separation. These emulsion gels were then used to coencapsulate a hydrophilic bioactive (epigallocatechin-3-gallate, EGCG) in the internal aqueous phase (encapsulation efficiency = 65.5%) and a hydrophobic bioactive (quercetin) in the oil phase (encapsulation efficiency = 97.2%). The emulsion gels improved EGCG chemical stability and quercetin solubility under simulated gastrointestinal conditions, which led to a 2- and 4-fold increase in their effective bioaccessibility, respectively.

Synthesis, characterization and cytotoxic studies of water soluble [(η5-C5H5)2Mo(thionucleobase/thionucleoside)]Cl complexes in breast and colon cancer cell lines

PubMed Central

Acevedo-Acevedo, Débora; Matta, Jaime; Meléndez, Enrique

2010-01-01

Four new water soluble molybdenocene complexes were synthesized in aqueous solution at pH 7.0. The new species, [(η5-C5H5)2Mo(L)]Cl (L= 6-mercaptopurine, 2-amino-6-mercaptopurine, (-)-2-amino-6-mercaptopurine ribose and 6-mercaptopurine ribose), were characterized by spectroscopic methods. NMR spectroscopic data showed the presence of two coordination isomers, S(6), N(7) and S(6), N(1), in aqueous solution, being S(6), N(7) the most stable. The antiproliferative activities of the new species were investigated in HT-29 colon and MCF-7 breast cancer cell lines. The incorporation of molybdenocene (Cp2Mo2+) into the thionucleobases/thionucleosides decreases their cytotoxic activities in HT-29 colon cancer cell line. In contrast, in the MCF-7 cell line, [Cp2Mo(2-amino-6-mercaptopurine)]Cl showed a high cytotoxic activity. This is most likely a consequence of the enhanced lipophilic character on the thionucleobase combined with synergism between Cp2Mo2+ and the thionucleobase ligand. PMID:21399723

Stimulus-responsive liposomes as smart nanoplatforms for drug delivery applications.

PubMed

Zangabad, Parham Sahandi; Mirkiani, Soroush; Shahsavari, Shayan; Masoudi, Behrad; Masroor, Maryam; Hamed, Hamid; Jafari, Zahra; Taghipour, Yasamin Davatgaran; Hashemi, Hura; Karimi, Mahdi; Hamblin, Michael R

2018-02-01

Liposomes are known to be promising nanoparticles (NPs) for drug delivery applications. Among different types of self-assembled NPs, liposomes stand out for their non-toxic nature, and their possession of dual hydrophilic-hydrophobic domains. Advantages of liposomes include the ability to solubilize hydrophobic drugs, the ability to incorporate different hydrophilic and lipophilic drugs at the same time, lessening the exposure of host organs to potentially toxic drugs and allowing modification of the surface by a variety of different chemical groups. This modification of the surface, or of the individual constituents, may be used to achieve two important goals. Firstly, ligands for active targeting can be attached that are recognized by cognate receptors over-expressed on the target cells of tissues. Secondly, modification can be used to impart a stimulus-responsive or "smart" character to the liposomes, whereby the cargo is released on demand only when certain internal stimuli (pH, reducing agents, specific enzymes) or external stimuli (light, magnetic field or ultrasound) are present. Here, we review the field of smart liposomes for drug delivery applications.

Liposomal Encapsulation Enzymes: From Medical Applications to Kinetic Characteristics.

PubMed

Jahadi, M; Khosravi-Darani, K

2017-01-01

Liposomes and nanoliposomes as small vesicles composed of phospholipid bilayer (entrapping one or more hydrophilic or lipophilic components) have recently found several potential applications in medicine and food industry. These vesicles may protect the core materials from moisture, heat and other extreme conditions. They may also provide controlled release of various bioactive agents, including food ingredients at the right place and time. Potential applications of enzyme-loaded liposomes are in the medical or biomedical field, particularly for the enzymereplacement therapy, as well as cheese industry for production of functional foods with improved health beneficial impacts on the consumer. Encapsulation process has a recondite impact on enzymes. In fact, liposome preparation techniques may alter the pH and temperature optima, affinity of the enzyme to substrate (Km), and maximum rate of reaction (Vmax). In addition, in this paper, the impact of process variables on the kinetic characteristics of enzymes encapsulated in liposomes was investigated. Also, the effects of enzyme entrapment in liposomes, prepared by different methods, on the catalytic efficiency of enzyme, as well as its kinetic properties and stability compared to native (free) enzymes has been reviewed.

Lecithins - promising oil spill cleaner

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

A new, non-polluting method of cleaning up oil spills at sea as well as on land has been developed by researchers at the Hebrew University of Jerusalem. Their technique is based on the use of lecithins, a byproduct of producing edible oils from plants. Lecithin molecules are hydrophyllic at one end and lipophilic at their tail ends. When they come into contact with water, they organize themselves into bilayers whose heads all face the water and whose tails are all directed towards each other. These bilayers form particles called liposomes that, when spread on water fouled by oil spills, changemore » the properties of the oil thereby stopping the spreading and breaking it down into sticky droplets that continue to float on the surface and can be easily collected. The treatment is said to be effective in both fresh and salt water and is almost temperature and pH independent. Another beneficial effect is that the physical change generated by liposomes in the spilled oil improves the ability of oil-eating bacteria in the water to remove some of the spill by bioremediation.« less

Pilot-scale resin adsorption as a means to recover and fractionate apple polyphenols.

PubMed

Kammerer, Dietmar R; Carle, Reinhold; Stanley, Roger A; Saleh, Zaid S

2010-06-09

The purification and fractionation of phenolic compounds from crude plant extracts using a food-grade acrylic adsorbent were studied at pilot-plant scale. A diluted apple juice concentrate served as a model phenolic solution for column adsorption and desorption trials. Phenolic concentrations were evaluated photometrically using the Folin-Ciocalteu assay and by HPLC-DAD. Recovery rates were significantly affected by increasing phenolic concentrations of the feed solutions applied to the column. In contrast, the flow rate during column loading hardly influenced adsorption efficiency, whereas the temperature and pH value were shown to be crucial parameters determining both total phenolic recovery rates and the adsorption behavior of individual polyphenols. As expected, the eluent composition had the greatest impact on the desorption characteristics of both total and individual phenolic compounds. HPLC analyses revealed significantly different elution profiles of individual polyphenols depending on lipophilicity. This technique allows fractionation of crude plant phenolic extracts, thus providing the opportunity to design the functional properties of the resulting phenolic fractions selectively, and the present study delivers valuable information with regard to the adjustment of individual process parameters.

Characterization of the Physicochemical Properties of β-Cyclodextrin-Divinyl Sulfone Polymer Carrier-Bile Acid Systems.

PubMed

Mohamed, Mohamed H; Wang, Chen; Peru, Kerry M; Headley, John V; Wilson, Lee D

2017-08-07

Herein, we report on the systematic design and characterization of cross-linked polymer carriers containing β-cyclodextrin (β-CD) and divinyl sulfone (DVS). The polymer carriers were prepared at variable feed ratios (β-CD-DVS; 1:1, 1:2, 1:3, and 1:6) and characterized using spectroscopy (IR, 1 H solution NMR, and 13 C CP-MAS solids NMR spectroscopy), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and a dye decolorization method using phenolphthalein. Uptake studies were carried out at pH 9.00 for the polymer carriers using single component bile acids (cholic acid, deoxycholic acid, glycodeoxycholic acid, and taurodeoxycholic acid). Equilibrium uptake results were evaluated by the Langmuir isotherm model where variable equilibrium parameters were related to the relative apolar character of the bile acid. The Langmuir model yields a carrier/bile acid binding affinity of ∼10 3 M -1 where the lipophilic inclusion sites of the polymer play a prominent role, while the DVS linker framework sites have a lower adsorption affinity, in accordance with the greater hydrophilic character of such sites.

Lipophilic Chemicals from Diesel Exhaust Particles Trigger Calcium Response in Human Endothelial Cells via Aryl Hydrocarbon Receptor Non-Genomic Signalling

PubMed Central

Le Ferrec, Eric; Podechard, Normand; Lagadic-Gossmann, Dominique; Shoji, Kenji F.; Kukowski, Klara; Holme, Jørn A.; Øvrevik, Johan

2018-01-01

Exposure to diesel exhaust particles (DEPs) affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca2+]i is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM) on [Ca2+]i and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with n-hexane (n-Hex-EOM), dichloromethane (DCM-EOM), methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the n-Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in n-Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1) using micro-spectrofluorometry. The lipophilic n-Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca2+]i increases in HMEC-1. n-Hex-EOM triggered [Ca2+]i increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE). By contrast, the less lipophilic DCM-EOM triggered [Ca2+]i increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE). Both extracts increased [Ca2+]i via aryl hydrocarbon receptor (AhR) non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca2+]i increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by n-hexane and DCM seem to induce rapid AhR-dependent [Ca2+]i increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction extracted by DCM also caused an AhR-dependent reduction in global membrane order, which appeared to be connected to the [Ca2+]i increase. PMID:29748474

Lipophilic Chemicals from Diesel Exhaust Particles Trigger Calcium Response in Human Endothelial Cells via Aryl Hydrocarbon Receptor Non-Genomic Signalling.

PubMed

Brinchmann, Bendik C; Le Ferrec, Eric; Podechard, Normand; Lagadic-Gossmann, Dominique; Shoji, Kenji F; Penna, Aubin; Kukowski, Klara; Kubátová, Alena; Holme, Jørn A; Øvrevik, Johan

2018-05-10

Exposure to diesel exhaust particles (DEPs) affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca 2+ ] i is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM) on [Ca 2+ ] i and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with n -hexane ( n -Hex-EOM), dichloromethane (DCM-EOM), methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the n -Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in n -Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1) using micro-spectrofluorometry. The lipophilic n -Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca 2+ ] i increases in HMEC-1. n -Hex-EOM triggered [Ca 2+ ] i increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE). By contrast, the less lipophilic DCM-EOM triggered [Ca 2+ ] i increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE). Both extracts increased [Ca 2+ ] i via aryl hydrocarbon receptor (AhR) non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca 2+ ] i increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by n -hexane and DCM seem to induce rapid AhR-dependent [Ca 2+ ] i increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction extracted by DCM also caused an AhR-dependent reduction in global membrane order, which appeared to be connected to the [Ca 2+ ] i increase.

Supercritical Carbon Dioxide and Microwave-Assisted Extraction of Functional Lipophilic Compounds from Arthrospira platensis

PubMed Central

Esquivel-Hernández, Diego A.; López, Víctor H.; Rodríguez-Rodríguez, José; Alemán-Nava, Gibrán S.; Cuéllar-Bermúdez, Sara P.; Rostro-Alanis, Magdalena; Parra-Saldívar, Roberto

2016-01-01

Arthrospira platensis biomass was used in order to obtain functional lipophilic compounds through green extraction technologies such as supercritical carbon dioxide fluid extraction (SFE) and microwave-assisted extraction (MAE). The temperature (T) factor was evaluated for MAE, while for SFE, pressure (P), temperature (T), and co-solvent (ethanol) (CS) were evaluated. The maximum extraction yield of the obtained oleoresin was (4.07% ± 0.14%) and (4.27% ± 0.10%) for SFE and MAE, respectively. Extracts were characterized by gas chromatography mass spectrometry (GC-MS) and gas chromatography flame ionization detector (GC-FID). The maximum contents of functional lipophilic compounds in the SFE and MAE extracts were: for carotenoids 283 ± 0.10 μg/g and 629 ± 0.13 μg/g, respectively; for tocopherols 5.01 ± 0.05 μg/g and 2.46 ± 0.09 μg/g, respectively; and for fatty acids 34.76 ± 0.08 mg/g and 15.88 ± 0.06 mg/g, respectively. In conclusion, the SFE process at P 450 bar, T 60 °C and CS 53.33% of CO2 produced the highest yield of tocopherols, carotenoids and fatty acids. The MAE process at 400 W and 50 °C gives the best extracts in terms of tocopherols and carotenoids. For yield and fatty acids, the MAE process at 400 W and 70 °C produced the highest values. Both SFE and MAE showed to be suitable green extraction technologies for obtaining functional lipophilic compounds from Arthrospira platensis. PMID:27164081

An in vitro skin sensitization assay termed EpiSensA for broad sets of chemicals including lipophilic chemicals and pre/pro-haptens.

PubMed

Saito, Kazutoshi; Takenouchi, Osamu; Nukada, Yuko; Miyazawa, Masaaki; Sakaguchi, Hitoshi

2017-04-01

To evaluate chemicals (e.g. lipophilic chemicals, pre/pro-haptens) that are difficult to correctly evaluate using in vitro skin sensitization tests (e.g. DPRA, KeratinoSens or h-CLAT), we developed a novel in vitro test termed "Epidermal Sensitization Assay: EpiSensA" that uses reconstructed human epidermis. This assay is based on the induction of multiple marker genes (ATF3, IL-8, DNAJB4 and GCLM) related to two keratinocyte responses (inflammatory or cytoprotective) in the induction of skin sensitization. Here, we first confirmed the mechanistic relevance of these marker genes by focusing on key molecules that regulate keratinocyte responses in vivo (P2X 7 for inflammatory and Nrf2 for cytoprotective responses). The up-regulation of ATF3 and IL-8, or DNAJB4 and GCLM induced by the representative sensitizer 2,4-dinitrochlorobenzene in human keratinocytes was significantly suppressed by a P2X 7 specific antagonist KN-62, or by Nrf2 siRNA, respectively, which supported mechanistic relevance of marker genes. Moreover, the EpiSensA had sensitivity, specificity and accuracy of 93%, 100% and 93% for 29 lipophilic chemicals (logKow≥3.5), and of 96%, 75% and 88% for 43 hydrophilic chemicals including 11 pre/pro-haptens, compared with the LLNA. These results suggested that the EpiSensA could be a mechanism-based test applicable to broad sets of chemicals including lipophilic chemicals and pre/pro-haptens. Copyright © 2016 Elsevier Ltd. All rights reserved.

PYRIDOXAMINE ANALOGS SCAVENGE LIPID-DERIVED γ-KETOALDEHYDES AND PROTECT AGAINST H2O2-MEDIATED CYTOTOXICITY†

PubMed Central

Davies, Sean S.; Brantley, Eric J.; Voziyan, Paul A.; Amarnath, Venkataraman; Zagol-Ikapitte, Irene; Boutaud, Olivier; Hudson, Billy G.; Oates, John A.; Jackson Roberts, L.

2008-01-01

Isoketals and levuglandins are highly reactive γ-ketoaldehydes formed by oxygenation of arachidonic acid in settings of oxidative injury and cyclooxygenase activation, respectively. These compounds rapidly adduct to proteins via lysyl residues, which can alter protein structure/function. We examined whether pyridoxamine, which has been shown to scavenge α-ketoaldehydes formed by carbohydrate or lipid peroxidation, could also effectively protect proteins from the more reactive γ-ketoaldehydes. Pyridoxamine prevented adduction of ovalbumin and also prevented inhibition of RNase A and glutathione reductase activity by the synthetic γ-ketoaldehyde, 15-E2-isoketal. We identified the major products of the reaction of pyridoxamine with the 15-E2-isoketal, including a stable lactam adduct. Two lipophilic analogs of pyridoxamine, salicylamine and 5’O-pentylpyridoxamine, also formed lactam adducts when reacted with 15-E2-isoketal. When we oxidized arachidonic acid in the presence of pyridoxamine or its analogs, pyridoxamine-isoketal adducts were found in significantly greater abundance than the pyridoxamine-N-acyl adducts formed by α-ketoaldehyde scavenging. Therefore, pyridoxamine and its analogs appear to preferentially scavenge γ-ketoaldehydes. Both pyridoxamine and its lipophilic analogs inhibited the formation of lysyl-levuglandin adducts in platelets activated ex vivo with arachidonic acid. The two lipophilic pyridoxamine analogs provided significant protection against H2O2-mediated cytotoxicity in HepG2 cells. These results demonstrate the utility of pyridoxamine and lipophilic pyridoxamine analogs to assess the potential contributions of isoketals and levuglandins in oxidant injury and inflammation and suggest their potential utility as pharmaceutical agents in these conditions. PMID:17176098

Simultaneous total antioxidant capacity assay of lipophilic and hydrophilic antioxidants in the same acetone-water solution containing 2% methyl-beta-cyclodextrin using the cupric reducing antioxidant capacity (CUPRAC) method.

PubMed

Ozyürek, Mustafa; Bektaşoğlu, Burcu; Güçlü, Kubilay; Güngör, Nilay; Apak, Reşat

2008-12-07

Antioxidants are health beneficial compounds that can protect cells from the damage caused by unstable molecules known as reactive oxygen species (ROS). This work reports the capacity assay of both lipophilic and hydrophilic antioxidants simultaneously, by making use of their 'host-guest' complexes with methyl-beta-cyclodextrin (M-beta-CD), a cyclic oligosaccharide, in acetonated aqueous medium using the cupric reducing antioxidant capacity (CUPRAC) method. Thus the order of antioxidant potency of various compounds irrespective of their lipophilicity could be established in the same solvent medium. M-beta-CD was introduced as the water solubility enhancer for lipophilic antioxidants. Two percent M-beta-CD (w/v) in an acetone-H(2)O (9:1, v/v) mixture was found to sufficiently solubilize beta-carotene, lycopene, vitamin E, vitamin C, synthetic antioxidants and other phenolic antioxidants. This assay was validated through linearity, additivity, precision, and recovery. The validation results demonstrate that the CUPRAC assay is reliable and robust. In acetonated aqueous solution of M-beta-CD, only CUPRAC and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays were capable of measuring carotenoids together with hydrophilic antioxidants. The CUPRAC antioxidant capacities of a wide range of polyphenolics and flavonoids were experimentally reported in this work as trolox equivalent antioxidant capacity (TEAC) in the CUPRAC assay, and compared to those found by reference methods, ABTS/horseradish peroxidase (HRP)-H(2)O(2) and ferric reducing antioxidant power (FRAP) assays.

Engineering and validation of a novel lipid thin film for biomembrane modeling in lipophilicity determination of drugs and xenobiotics

PubMed Central

Idowu, Sunday Olakunle; Adeyemo, Morenikeji Ambali; Ogbonna, Udochi Ihechiluru

2009-01-01

Background Determination of lipophilicity as a tool for predicting pharmacokinetic molecular behavior is limited by the predictive power of available experimental models of the biomembrane. There is current interest, therefore, in models that accurately simulate the biomembrane structure and function. A novel bio-device; a lipid thin film, was engineered as an alternative approach to the previous use of hydrocarbon thin films in biomembrane modeling. Results Retention behavior of four structurally diverse model compounds; 4-amino-3,5-dinitrobenzoic acid (ADBA), naproxen (NPX), nabumetone (NBT) and halofantrine (HF), representing 4 broad classes of varying molecular polarities and aqueous solubility behavior, was investigated on the lipid film, liquid paraffin, and octadecylsilane layers. Computational, thermodynamic and image analysis confirms the peculiar amphiphilic configuration of the lipid film. Effect of solute-type, layer-type and variables interactions on retention behavior was delineated by 2-way analysis of variance (ANOVA) and quantitative structure property relationships (QSPR). Validation of the lipid film was implemented by statistical correlation of a unique chromatographic metric with Log P (octanol/water) and several calculated molecular descriptors of bulk and solubility properties. Conclusion The lipid film signifies a biomimetic artificial biological interface capable of both hydrophobic and specific electrostatic interactions. It captures the hydrophilic-lipophilic balance (HLB) in the determination of lipophilicity of molecules unlike the pure hydrocarbon film of the prior art. The potentials and performance of the bio-device gives the promise of its utility as a predictive analytic tool for early-stage drug discovery science. PMID:19735551

Determination of reversed-phase high performance liquid chromatography based octanol-water partition coefficients for neutral and ionizable compounds: Methodology evaluation.

PubMed

Liang, Chao; Qiao, Jun-Qin; Lian, Hong-Zhen

2017-12-15

Reversed-phase liquid chromatography (RPLC) based octanol-water partition coefficient (logP) or distribution coefficient (logD) determination methods were revisited and assessed comprehensively. Classic isocratic and some gradient RPLC methods were conducted and evaluated for neutral, weak acid and basic compounds. Different lipophilicity indexes in logP or logD determination were discussed in detail, including the retention factor logk w corresponding to neat water as mobile phase extrapolated via linear solvent strength (LSS) model from isocratic runs and calculated with software from gradient runs, the chromatographic hydrophobicity index (CHI), apparent gradient capacity factor (k g ') and gradient retention time (t g ). Among the lipophilicity indexes discussed, logk w from whether isocratic or gradient elution methods best correlated with logP or logD. Therefore logk w is recommended as the preferred lipophilicity index for logP or logD determination. logk w easily calculated from methanol gradient runs might be the main candidate to replace logk w calculated from classic isocratic run as the ideal lipophilicity index. These revisited RPLC methods were not applicable for strongly ionized compounds that are hardly ion-suppressed. A previously reported imperfect ion-pair RPLC method was attempted and further explored for studying distribution coefficients (logD) of sulfonic acids that totally ionized in the mobile phase. Notably, experimental logD values of sulfonic acids were given for the first time. The IP-RPLC method provided a distinct way to explore logD values of ionized compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

Lipophilization of somatostatin analog RC-160 with long chain fatty acid improves its antiproliferative and antiangiogenic activity in vitro.

PubMed

Dasgupta, P; Mukherjee, R

2000-01-01

The therapeutic potential of the somatostatin analogue RC-160 having antiproliferative activity, is limited by its short serum half life. To overcome this limitation, fatty acids namely butanoic acid and myristic acid were conjugated to the N-terminal residue of RC-160. The lipophilized derivatives of RC-160 were synthesized, purified by reverse phase HPLC and characterized by ES-mass spectroscopy. The antiproliferative activity of lipophilized derivatives of RC-160 on the growth of MIA-PaCa2 (human pancreatic carcinoma), DU145 (human prostate carcinoma), ECV304 (human umbilical chord endothelioma), as well as their antiangiogenic activity was evaluated in vitro. The relative stability of myristoyl-RC-160 towards degradation by proteases and serum was also determined. Myristoyl-RC-160 exhibited significantly higher antiproliferative efficacy than RC-160, on the above cell lines (P<0.01). Receptor binding assays, demonstrated that the affinity of RC-160 towards somatostatin receptors remains unaltered by myristoylation. Unlike RC-160, the myristoylated derivative was found to have significantly greater resistance to protease and serum degradation (P<0.01). Myristoyl-RC-160 exhibited significantly greater antiproliferative activity on ECV304, than RC-160 (P<0.01). Myristoyl RC-160 could also inhibit capillary tube formation more efficiently than RC-160 in a dose dependent manner, suggesting that it possessed enhanced antiangiogenic activity in vitro (P<0.001). Lipophilization of RC-160 with long chain fatty acids like myristic acid endows it with improved antiproliferative and antiangiogenic activity, stability and therapeutic index. British Journal of Pharmacology (2000) 109, 101 - 109

Lipophilization of somatostatin analog RC-160 with long chain fatty acid improves its antiproliferative and antiangiogenic activity in vitro

PubMed Central

Dasgupta, P; Mukherjee, R

2000-01-01

The therapeutic potential of the somatostatin analogue RC-160 having antiproliferative activity, is limited by its short serum half life. To overcome this limitation, fatty acids namely butanoic acid and myristic acid were conjugated to the N-terminal residue of RC-160. The lipophilized derivatives of RC-160 were synthesized, purified by reverse phase HPLC and characterized by ES-mass spectroscopy. The antiproliferative activity of lipophilized derivatives of RC-160 on the growth of MIA-PaCa2 (human pancreatic carcinoma), DU145 (human prostate carcinoma), ECV304 (human umbilical chord endothelioma), as well as their antiangiogenic activity was evaluated in vitro. The relative stability of myristoyl-RC-160 towards degradation by proteases and serum was also determined. Myristoyl-RC-160 exhibited significantly higher antiproliferative efficacy than RC-160, on the above cell lines (P<0.01). Receptor binding assays, demonstrated that the affinity of RC-160 towards somatostatin receptors remains unaltered by myristoylation. Unlike RC-160, the myristoylated derivative was found to have significantly greater resistance to protease and serum degradation (P<0.01). Myristoyl-RC-160 exhibited significantly greater antiproliferative activity on ECV304, than RC-160 (P<0.01). Myristoyl RC-160 could also inhibit capillary tube formation more efficiently than RC-160 in a dose dependent manner, suggesting that it possessed enhanced antiangiogenic activity in vitro (P<0.001). Lipophilization of RC-160 with long chain fatty acids like myristic acid endows it with improved antiproliferative and antiangiogenic activity, stability and therapeutic index. PMID:10694208

Supercritical Carbon Dioxide and Microwave-Assisted Extraction of Functional Lipophilic Compounds from Arthrospira platensis.

PubMed

Esquivel-Hernández, Diego A; López, Víctor H; Rodríguez-Rodríguez, José; Alemán-Nava, Gibrán S; Cuéllar-Bermúdez, Sara P; Rostro-Alanis, Magdalena; Parra-Saldívar, Roberto

2016-05-05

Arthrospira platensis biomass was used in order to obtain functional lipophilic compounds through green extraction technologies such as supercritical carbon dioxide fluid extraction (SFE) and microwave-assisted extraction (MAE). The temperature (T) factor was evaluated for MAE, while for SFE, pressure (P), temperature (T), and co-solvent (ethanol) (CS) were evaluated. The maximum extraction yield of the obtained oleoresin was (4.07% ± 0.14%) and (4.27% ± 0.10%) for SFE and MAE, respectively. Extracts were characterized by gas chromatography mass spectrometry (GC-MS) and gas chromatography flame ionization detector (GC-FID). The maximum contents of functional lipophilic compounds in the SFE and MAE extracts were: for carotenoids 283 ± 0.10 μg/g and 629 ± 0.13 μg/g, respectively; for tocopherols 5.01 ± 0.05 μg/g and 2.46 ± 0.09 μg/g, respectively; and for fatty acids 34.76 ± 0.08 mg/g and 15.88 ± 0.06 mg/g, respectively. In conclusion, the SFE process at P 450 bar, T 60 °C and CS 53.33% of CO₂ produced the highest yield of tocopherols, carotenoids and fatty acids. The MAE process at 400 W and 50 °C gives the best extracts in terms of tocopherols and carotenoids. For yield and fatty acids, the MAE process at 400 W and 70 °C produced the highest values. Both SFE and MAE showed to be suitable green extraction technologies for obtaining functional lipophilic compounds from Arthrospira platensis.

The computation of lipophilicities of ⁶⁴Cu PET systems based on a novel approach for fluctuating charges.

PubMed

Comba, Peter; Martin, Bodo; Sanyal, Avik; Stephan, Holger

2013-08-21

A QSPR scheme for the computation of lipophilicities of ⁶⁴Cu complexes was developed with a training set of 24 tetraazamacrocylic and bispidine-based Cu(II) compounds and their experimentally available 1-octanol-water distribution coefficients. A minimum number of physically meaningful parameters were used in the scheme, and these are primarily based on data available from molecular mechanics calculations, using an established force field for Cu(II) complexes and a recently developed scheme for the calculation of fluctuating atomic charges. The developed model was also applied to an independent validation set and was found to accurately predict distribution coefficients of potential ⁶⁴Cu PET (positron emission tomography) systems. A possible next step would be the development of a QSAR-based biodistribution model to track the uptake of imaging agents in different organs and tissues of the body. It is expected that such simple, empirical models of lipophilicity and biodistribution will be very useful in the design and virtual screening of positron emission tomography (PET) imaging agents.

Microemulsions based on a sunflower lecithin-Tween 20 blend have high capacity for dissolving peppermint oil and stabilizing coenzyme Q10.

PubMed

Chen, Huaiqiong; Guan, Yongguang; Zhong, Qixin

2015-01-28

The objectives of the present study were to improve the capability of microemulsions to dissolve peppermint oil by blending sunflower lecithin with Tween 20 and to study the possibility of codelivering lipophilic bioactive compounds. The oil loading in microemulsions with 20% (w/w) Tween 20 increased from 3% (w/w) to 20% (w/w) upon gradual supplementation of 6% (w/w) lecithin. All microemulsions had particles of <12 nm that did not change over 70 d of storage at 21 °C. They had relatively low Newtonian viscosities and were physically and chemically stable after 50-200-fold dilution in water, resulting from similar hydrophile-lipophile-balance values of the surfactant mixture and peppermint oil. Furthermore, the microemulsions were capable of dissolving coenzyme Q10 and preventing its degradation at UV 302 nm, more significant for the microemulsion with lecithin. Therefore, natural surfactant lecithin can reduce the use of synthetic Tween 20 to dissolve peppermint oil and protect the degradation of dissolved lipophilic bioactive components in transparent products.

Nanostructuring Biomaterials with Specific Activities towards Digestive Enzymes for Controlled Gastrointestinal Absorption of Lipophilic Bioactive Molecules.

PubMed

Joyce, Paul; Whitby, Catherine P; Prestidge, Clive A

2016-11-01

This review describes the development of novel lipid-based biomaterials that modulate fat digestion for the enhanced uptake of encapsulated lipophilic bioactive compounds (e.g. drugs and vitamins). Specific focus is directed towards analysing how key material characteristics affect the biological function of digestive lipases and manipulate lipolytic digestion. The mechanism of lipase action is a complex, interfacial process, whereby hydrolysis can be controlled by the ability for lipase to access and adsorb to the lipid-in-water interface. However, significant conjecture exists within the literature regarding parameters that influence the activities of digestive lipases. Important findings from recent investigations that strategically examined the interplay between the interfacial composition of the lipid microenvironment and lipolysis kinetics in simulated biophysical environments are presented. The correlation between lipolysis and the rate of solubilisation and absorption of lipophilic compounds in the gastrointestinal tract (GIT) is detailed. Greater insights into the mechanism of lipase action have provided a new approach for designing colloidal carriers that orally deliver poorly soluble compounds, directly impacting the pharmaceutical and food industries. Copyright © 2016 Elsevier B.V. All rights reserved.

Interaction of xenobiotics on the glucose-transport system and the Na+/K(+)-ATPase of human skin fibroblasts.

PubMed

Cascorbi, I; Forêt, M

1991-02-01

The effects of individual and combined xenobiotics on functional properties of the plasma membrane of human skin fibroblasts were investigated. Good correlations between toxic effects on the D-glucose transport system or the Na+/K(+)-ATPase and the lipophilicity of the substances could be observed. The linear regression coefficients plotting log EC20 values (doses, leading to 20% inhibition) versus log Pow (octanol/water partition coefficient) were r = 0.95 (P less than 0.05). The combination of lipophilic with less lipophilic xenobiotics, such as pentachlorophenol with 4-chloroaniline, leads to additional effects. However, when the detergent sodium dodecyl benzenesulfonate was combined with the herbicide 2,4-dichlorophenoxyacetate (2,4-D), the toxic effect of 2,4-D on the Na+/K(+)-ATPase decreased considerably. The results support in general the assumption that the inhibition of integral functional proteins is based on an accumulation of xenobiotics in the plasma membrane, probably due to the enhanced membrane fluidity. Thus, the basic toxicity of xenobiotics can be predicted by their physicochemical properties.

Optimisation of cosolvent concentration for topical drug delivery III--influence of lipophilic vehicles on ibuprofen permeation.

PubMed

Watkinson, R M; Guy, R H; Oliveira, G; Hadgraft, J; Lane, M E

2011-01-01

Previously, we have reported the effects of water, ethanol, propylene glycol and various binary and ternary mixtures of these solvents on the permeation of ibuprofen in model membranes and in skin. The present study investigates the influence of lipophilic vehicles on the transport of ibuprofen in silicone membrane and in human skin. The permeation of ibuprofen was measured from mineral oil (MO), Miglyol® 812 (MG) and binary mixtures of MO and MG. The solubility of ibuprofen was 5-fold higher in MG than in MO, however, the permeation of ibuprofen from the pure vehicles and combinations of both was comparable in silicone membrane. Additionally, there were no significant differences in skin permeation for MO and MG vehicles. When the permeation of various hydrophilic and lipophilic vehicles is considered, a trend between flux values for the model membrane and skin is evident (r(2) = 0.71). The findings suggest that silicone membrane may provide information on qualitative trends in skin permeation for vehicles of diverse solubility and partition characteristics. Copyright © 2010 S. Karger AG, Basel.

Enhanced antiamyloidal activity of hydroxy cinnamic acids by enzymatic esterification with alkyl alcohols.

PubMed

Kondo, Hazuki; Sugiyama, Haruka; Katayama, Shigeru; Nakamura, Soichiro

2014-01-01

Lipophilic derivatives of hydroxyl cinnamic acids (HCAs) including caffeic acid (CA), ferulic acid, sinapic acid (SA), and chlorogenic acid were synthesized by esterification with butanol, octanol, or hexadecanol catalyzed by the lipase from Candida antarctica to investigate the effect of lipophilicity on their antiamyloidal activity assessed by the inhibitory activities toward fibrillization of amyloid β (Aβ) peptide. Among them, CA showed the highest activity at 50 μM, reducing the amyloid fibril formation of Aβ to 34.4 ± 6.8%. The antiamyloidal effects of HCAs were enhanced by esterification with alkyl alcohols, and the longer alkyl chain tended to be more effective except for SA. Aβ fibril formation was suppressed by the hexadecyl ester of CA, which was reduced to 8.8 ± 2.3%. In contrast, those of octyl and butyl esters were 19.3 ± 2.3% and 41.6 ± 6.1%, respectively. These results show that lipophilicity plays an important role in the antiamyloidal activities of esterified phenolic compounds. © 2013 International Union of Biochemistry and Molecular Biology, Inc.

Simultaneous microencapsulation of hydrophilic and lipophilic bioactives in liposomes produced by an ecofriendly supercritical fluid process.

PubMed

Tsai, Wen-Chyan; Rizvi, Syed S H

2017-09-01

Organic solvent residues are always a concern with the liposomes produced by traditional techniques. Our objectives were to encapsulate hydrophilic and lipophilic compounds in liposomes using a newly designed supercritical fluid process coupled with vacuum-driven cargo loading. Supercritical carbon dioxide was chosen as the phospholipid-dissolving medium and an ecofriendly substitute for organic solvents. Liposomal microencapsulation was conducted via a 1000-μm expansion nozzle at 12.41MPa, 90°C, and aqueous cargo loading rate of 0.25ml/s. Vitamins C and E were selected as model hydrophilic and lipophilic compounds encapsulated in the integrated liposomes. The average vesicle size was 951.02nm with a zeta potential of -51.87mV. The encapsulation efficiency attained was 32.97% for vitamin C and 99.32% for vitamin E. Good emulsion stability was maintained during storage at 4°C for 20days. Simultaneous microencapsulation in the liposomes was successfully achieved with this supercritical fluid process. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lipids, tocopherols, and carotenoids in leaves of amaranth and quinoa cultivars and a new approach to overall evaluation of nutritional quality traits.

PubMed

Tang, Yao; Li, Xihong; Chen, Peter X; Zhang, Bing; Hernandez, Marta; Zhang, Hua; Marcone, Massimo F; Liu, Ronghua; Tsao, Rong

2014-12-31

Composition of lipophilic phytochemicals including fatty acids, tocopherols, and carotenoids in leaves of 6 quinoa and 14 amaranth cultivars was analyzed. The oil yields in quinoa and amaranth leaves were only 2.72-4.18%, which contained mainly essential fatty acids and had a highly favorable ω-3/ω-6 ratio (2.28-3.89). Pro-vitamin A carotenoids, mainly α- and β-carotenes, and xanthophylls, predominantly lutein and violaxanthin, were found in all samples. The primary tocopherol isomers present in both quinoa and amaranth leaves were α- and β-tocopherols. Added to the discussion on the lipophilic nutrients was the normalization of ω-3/ω-6 ratio, α-tocopherol equivalents, and carotenoids, in an attempt to establish a novel system for evaluation of the overall quality attributes of lipophilic nutrients (NQ value). The NQ value, but not the individual components, was highly correlated with all the antioxidant activities, supporting the ranking order of the potential nutritional quality of quinoa and amaranth leaves based on this new method.

Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides.

PubMed

De Marco, Agostino; De Candia, Modesto; Carotti, Andrea; Cellamare, Saverio; De Candia, Erica; Altomare, Cosimo

2004-06-01

Using N-[4-(hexyloxy)phenyl]piperidine-3-carboxamide (17c) as a structural lead, a number of isomers, derivatives, and ring-opened analogs were synthesized and tested for their ability to block the in vitro aggregation of human platelets induced by adenosine 5'-diphosphate (ADP). For the most active compounds, inhibition of the platelet aggregation triggered by arachidonic acid (AA) and ADP-induced intraplatelet calcium mobilization was also demonstrated. Based on quantitative structure-activity relationships (QSARs), we proved the impact of hydrophobicity on antiplatelet activity by a nonlinear (parabolic or bilinear) relationship between pIC(50) and lipophilicity, as assessed by RP-HPLC capacity factors and ClogP (i.e. calculated 1-octanol-water partition coefficients). This study highlighted the following additional SARs: quasi-isolipophilic isomers of 17c (isonipecotanilides and pipecolinanilides) and ring-opened analogs (e.g. anilide of beta-alanine) exhibited lower antiplatelet activity; methylation of the piperidine nitrogen of 17c has no effect, whereas alkylation with an n-propyl group decreases the activity by a factor of approximately 2, most likely due to a conformation-dependent decrease in lipophilicity.

Different effectiveness of two pastas supplemented with either lipophilic or hydrophilic/phenolic antioxidants in affecting serum as evaluated by the novel Antioxidant/Oxidant Balance approach.

PubMed

Laus, Maura N; Soccio, Mario; Alfarano, Michela; Pasqualone, Antonella; Lenucci, Marcello S; Di Miceli, Giuseppe; Pastore, Donato

2017-04-15

Effectiveness in improving serum antioxidant status of two functional pastas was evaluated by the novel Antioxidant/Oxidant Balance (AOB) parameter, calculated as Antioxidant Capacity (AC)/Peroxide Level ratio, assessed here for the first time. In particular, Bran Oleoresin (BO) and Bran Water (BW) pastas, enriched respectively with either lipophilic (tocochromanols, carotenoids) or hydrophilic/phenolic antioxidants extracted from durum wheat bran, were studied. Notably, BO pasta was able to improve significantly (+65%) serum AOB during four hours after intake similarly to Lisosan G, a wheat antioxidant-rich dietary supplement. Contrarily, BW pasta had oxidative effect on serum so as conventional pasta and glucose, thus suggesting greater effectiveness of lipophilic than hydrophilic/phenolic antioxidants under our experimental conditions. Interestingly, no clear differences between the two pastas were observed, when AC measurements of either serum after pasta intake or pasta extracts by in vitro assays were considered, thus strengthening effectiveness and reliability of AOB approach. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lipophilization of ascorbic acid: a monolayer study and biological and antileishmanial activities.

PubMed

Kharrat, Nadia; Aissa, Imen; Sghaier, Manel; Bouaziz, Mohamed; Sellami, Mohamed; Laouini, Dhafer; Gargouri, Youssef

2014-09-17

Ascorbyl lipophilic derivatives (Asc-C2 to Asc-C(18:1)) were synthesized in a good yield using lipase from Staphylococcus xylosus produced in our laboratory and immobilized onto silica aerogel. Results showed that esterification had little effect on radical-scavenging capacity of purified ascorbyl esters using DPPH assay in ethanol. However, long chain fatty acid esters displayed higher protection of target lipids from oxidation. Moreover, compared to ascorbic acid, synthesized derivatives exhibited an antibacterial effect. Furthermore, ascorbyl derivatives were evaluated, for the first time, for their antileishmanial effects against visceral (Leishmania infantum) and cutaneous parasites (Leishmania major). Among all the tested compounds, only Asc-C10, Asc-C12, and Asc-C(18:1) exhibited antileishmanial activities. The interaction of ascorbyl esters with a phospholipid monolayer showed that only medium and unsaturated long chain (Asc-C10 to Asc-C(18:1)) derivative esters were found to interact efficiently with mimetic membrane of leishmania. These properties would make ascorbyl derivatives good candidates to be used in cosmetic and pharmaceutical lipophilic formulations.

Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

PubMed Central

2014-01-01

N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization. PMID:24641010

Lipophilization of Hydroxytyrosol-Enriched Fractions from Olea europaea L. Byproducts and Evaluation of the in Vitro Effects on a Model of Colorectal Cancer Cells.

PubMed

Bernini, Roberta; Carastro, Isabella; Palmini, Gaia; Tanini, Annalisa; Zonefrati, Roberto; Pinelli, Patrizia; Brandi, Maria Luisa; Romani, Annalisa

2017-08-09

A hydroxytyrosol (HTyr)-enriched fraction containing HTyr 6% w/w, derived from Olea europaea L. byproducts and obtained using an environmentally and economically sustainable technology, was lipophilized under green chemistry conditions. The effects of three fractions containing hydroxytyrosyl butanoate, octanoate, and oleate, named, respectively, lipophilic fractions 5, 6, and 7, and unreacted HTyr on the human colon cancer cell line HCT8-β8 engineered to overexpress estrogen receptor β (ERβ) were evaluated and compared to those of pure HTyr. The experimental data demonstrated that HTyr and all fractions showed an antiproliferative effect, as had been observed by the evaluation of the cellular doubling time under these different conditions (mean control, 32 ± 4 h; HTyr 1, 65 ± 9 h; fraction 5, 64 ± 11 h; fraction 6, 62 ± 14 h; fraction 7, 133 ± 30 h). As evidenced, fraction 7 containing hydroxytyrosyl oleate showed the highest activity. These results were related to the link with ER-β, which was assessed through simultaneous treatment with an inhibitor of ERβ.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xia, Yifeng; Liu, Yi -Liang; Xie, Yonghua

Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not yet been successfully targeted. Here in this paper, we describe a combination therapy for treating these malignancies using two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of the KRAS and other small G-proteins critical for tumor growthmore » and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant NF-κB activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mTOR pathway, facilitated autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. Lastly, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations.« less

Synthesis and Characterization of a Novel Phenolic Lipid for Use as Potential Lipophilic Antioxidant and as a Prodrug of Butyric Acid.

PubMed

Kaki, Shiva Shanker; Kunduru, Konda Reddy; Kanjilal, Sanjit; Narayana Prasad, Rachapudi Badari

2015-01-01

Ferulic acid was modified to produce a novel phenolipid containing butyl chains. Ferulic acid was esterified with butanol to produce butyl ferulate which was further dihydroxylated followed by esterification with butyric anhydride to produce the phenolipid containing butyric acid. IR, NMR and MS techniques confirmed the structure of the synthesized structured lipophilic phenolic compound. The synthesized compound was tested for in vitro antioxidant and antimicrobial activities. The produced phenolipid showed moderate antioxidant activity in DPPH (2, 2-diphenyl-1-picrylhydrazyl) radical scavenging assay but in linoleic acid oxidation method, it exhibited good activity compared with the parent compound and the reference compounds. The prepared derivative could find applications as antioxidant in lipophilic systems and also as a potential prodrug of butyric acid. It also showed antibacterial effect against the four bacterial strains studied. The drug-likeness properties of the prepared molecule calculated were in the acceptable ranges according to Lipinski's rule of 5 and suggest that it has potential to cross the blood-brain barrier.

Lipophilic ternary complexes in liquid-liquid extraction of trivalent lanthanides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lumetta, Gregg J.; Levitskaia, Tatiana G.; Latesky, Stanley

2012-03-01

The formation of ternary complexes between lanthanide ions [Nd(III) or Eu(III)], octyl(phenyl)-N,N-diisobutyl-carbamoylmethylphosphine oxide (CMPO), and bis-(2-ethylhexyl)phosphoric acid (HDEHP) was probed by liquid-liquid extraction and spectroscopic techniques. Equilibrium modeling of data for the extraction of Nd(III) or Eu(III) from lactic acid media into n-dodecane solutions of CMPO and HDEHP indicates the predominant extracted species are of the type [Ln(AHA){sub 2}(A)] and [Ln(CMPO)(AHA){sub 2}(A)], where Ln = Nd or Eu and A represents the DEHP{sup -} anion. FTIR (for both Eu and Nd) and visible spectrophotometry (in the case of Nd) indicate the formation of the [Ln(CMPO)(A){sup 3}] complexes when CMPO ismore » added to n-dodecane solutions of the LnA{sub 3} compounds. Both techniques indicate a stronger propensity of CMPO to complex Nd(III) versus Eu(III).« less

Ciclosporin 10 years on: indications and efficacy

PubMed Central

Forsythe, Peter; Paterson, Sue

2014-01-01

Ciclosporin is a lipophilic cyclic polypeptide with powerful immunosuppressive and immunomodulatory properties that has been used in veterinary medicine for two decades. It is a calcineurin inhibitor whose principal mode of action is to inhibit T cell activation. The drug is principally absorbed from the small intestine and is metabolised in the intestine and liver by the cytochrome P450 enzyme system. Ciclosporin is known to interact with a wide range of pharmacological agents. Numerous studies have demonstrated good efficacy for the management of canine atopic dermatitis and this has been a licensed indication since 2003. In addition to the treatment of atopic dermatitis, it has been used as an aid in the management of numerous other dermatological conditions in animals including perianal fistulation, sebaceous adenitis, pododermatitis, chronic otitis externa and pemphigus foliaceus. This article reviews the mode of action, pharmacokinetics, indications for use and efficacy of ciclosporin in veterinary dermatology. PMID:24682697

The cluster [Re6Se8I6]3- penetrates biological membranes: drug-like properties for CNS tumor treatment and diagnosis.

PubMed

Estrada, Lisbell D; Duran, Elizabeth; Cisterna, Matias; Echeverria, Cesar; Zheng, Zhiping; Borgna, Vincenzo; Arancibia-Miranda, Nicolas; Ramírez-Tagle, Rodrigo

2018-03-24

Tumorigenic cell lines are more susceptible to [Re 6 Se 8 I 6 ] 3- cluster-induced death than normal cells, becoming a novel candidate for cancer treatment. Still, the feasibility of using this type of molecules in human patients remains unclear and further pharmacokinetics analysis is needed. Using coupled plasma optical emission spectroscopy, we determined the Re-cluster tissue content in injected mice, as a biodistribution measurement. Our results show that the Re-cluster successfully reaches different tissues, accumulating mainly in heart and liver. In order to dissect the mechanism underlying cluster biodistribution, we used three different experimental approaches. First, we evaluate the degree of lipophilicity by determining the octanol/water partition coefficient. The cluster mostly remained in the octanol fraction, with a coefficient of 1.86 ± 0.02, which indicates it could potentially cross cell membranes. Then, we measured the biological membrane penetration through a parallel artificial membrane permeability assays (PAMPA) assay. The Re-cluster crosses the artificial membrane, with a coefficient of 122 nm/s that is considered highly permeable. To evaluate a potential application of the Re-cluster in central nervous system (CNS) tumors, we analyzed the cluster's brain penetration by exposing cultured blood-brain-barrier (BBB) cells to increasing concentrations of the cluster. The Re-cluster effectively penetrates the BBB, reaching nearly 30% of the brain side after 24 h. Thus, our results indicate that the Re-cluster penetrates biological membranes reaching different target organs-most probably due to its lipophilic properties-becoming a promising anti-cancer drug with high potential for CNS cancer's diagnosis and treatment.

Transport of hop aroma compounds across Caco-2 monolayers.

PubMed

Heinlein, A; Metzger, M; Walles, H; Buettner, A

2014-11-01

Although being reported and used as a sedative remedy for several years, the bioactive principle of hop preparations is still not decisively clarified. Understanding absorption and transformation processes of potential physiologically active constituents is essential to evaluate the likeliness of biological effects on humans. Therefore, single hop aroma compounds as well as digestive transformation products thereof have been investigated in view of their human intestinal absorption, applying Caco-2 transport experiments as well as investigations on potential biotransformation processes. Selective and sensitive identification and quantification were thereby achieved by application of two-dimensional high resolution gas chromatography-mass spectrometry in conjunction with stable isotope dilution analysis, leading to the determination of apparent permeability values by different mathematical approaches considering sink and non-sink conditions. Overall, calculated permeability values ranged from 2.6 × 10(-6) to 1.8 × 10(-4) cm s(-1) with all mathematical approaches, indicating high absorption potential and almost complete bioavailability for all tested compounds with hydroxyl-functionalities. Considering this high permeability together with the high lipophilicity of these substances, a passive transcellular uptake route can be speculated. Investigated sesquiterpenes and β-myrcene showed flat absorption profiles while the investigated esters showed decreasing profiles. In view of the lipophilic and volatile nature of the investigated substances, special attention was paid to recovery and mass balance determination. Furthermore, in the course of the transport experiments of 1-octen-3-ol and 3-methyl-2-buten-1-ol, additional biotransformation products were observed, namely 3-octanone and 3-methyl-2-butenal, respectively. The absence of these additional substances in control experiments strongly indicates an intestinal first-pass metabolism of the α,β-unsaturated alcohols 1-octen-3-ol and 3-methyl-2-buten-1-ol in Caco-2 cells.

Thermodynamic Driving Force of Hydrogen on Rumen Microbial Metabolism: A Theoretical Investigation

PubMed Central

van Lingen, Henk J.; Plugge, Caroline M.; Fadel, James G.; Kebreab, Ermias; Bannink, André; Dijkstra, Jan

2016-01-01

Hydrogen is a key product of rumen fermentation and has been suggested to thermodynamically control the production of the various volatile fatty acids (VFA). Previous studies, however, have not accounted for the fact that only thermodynamic near-equilibrium conditions control the magnitude of reaction rate. Furthermore, the role of NAD, which is affected by hydrogen partial pressure (PH2), has often not been considered. The aim of this study was to quantify the control of PH2 on reaction rates of specific fermentation pathways, methanogenesis and NADH oxidation in rumen microbes. The control of PH2 was quantified using the thermodynamic potential factor (FT), which is a dimensionless factor that corrects a predicted kinetic reaction rate for the thermodynamic control exerted. Unity FT was calculated for all glucose fermentation pathways considered, indicating no inhibition of PH2 on the production of a specific type of VFA (e.g., acetate, propionate and butyrate) in the rumen. For NADH oxidation without ferredoxin oxidation, increasing PH2 within the rumen physiological range decreased FT from unity to zero for different NAD+ to NADH ratios and pH of 6.2 and 7.0, which indicates thermodynamic control of PH2. For NADH oxidation with ferredoxin oxidation, increasing PH2 within the rumen physiological range decreased FT from unity at pH of 7.0 only. For the acetate to propionate conversion, FT increased from 0.65 to unity with increasing PH2, which indicates thermodynamic control. For propionate to acetate and butyrate to acetate conversions, FT decreased to zero below the rumen range of PH2, indicating full thermodynamic suppression. For methanogenesis by archaea without cytochromes, FT differed from unity only below the rumen range of PH2, indicating no thermodynamic control. This theoretical investigation shows that thermodynamic control of PH2 on individual VFA produced and associated yield of hydrogen and methane cannot be explained without considering NADH oxidation. PMID:27783615

Influence of pH Regulation Mode in Glucose Fermentation on Product Selection and Process Stability.

PubMed

Mohd-Zaki, Zuhaida; Bastidas-Oyanedel, Juan R; Lu, Yang; Hoelzle, Robert; Pratt, Steven; Slater, Fran R; Batstone, Damien J

2016-01-04

Mixed culture anaerobic fermentation generates a wide range of products from simple sugars, and is potentially an effective process for producing renewable commodity chemicals. However it is difficult to predict product spectrum, and to control the process. One of the key control handles is pH, but the response is commonly dependent on culture history. In this work, we assess the impact of pH regulation mode on the product spectrum. Two regulation modes were applied: in the first, pH was adjusted from 4.5 to 8.5 in progressive steps of 0.5 and in the second, covered the same pH range, but the pH was reset to 5.5 before each change. Acetate, butyrate, and ethanol were produced throughout all pH ranges, but there was a shift from butyrate at pH < 6.5 to ethanol at pH > 6.5, as well as a strong and consistent shift from hydrogen to formate as pH increased. Microbial analysis indicated that progressive pH resulted in dominance by Klebsiella, while reset pH resulted in a bias towards Clostridium spp., particularly at low pH, with higher variance in community between different pH levels. Reset pH was more responsive to changes in pH, and analysis of Gibbs free energy indicated that the reset pH experiments operated closer to thermodynamic equilibrium, particularly with respect to the formate/hydrogen balance. This may indicate that periodically resetting pH conforms better to thermodynamic expectations.

Influence of pH Regulation Mode in Glucose Fermentation on Product Selection and Process Stability

PubMed Central

Mohd-Zaki, Zuhaida; Bastidas-Oyanedel, Juan R.; Lu, Yang; Hoelzle, Robert; Pratt, Steven; Slater, Fran R.; Batstone, Damien J.

2016-01-01

Mixed culture anaerobic fermentation generates a wide range of products from simple sugars, and is potentially an effective process for producing renewable commodity chemicals. However it is difficult to predict product spectrum, and to control the process. One of the key control handles is pH, but the response is commonly dependent on culture history. In this work, we assess the impact of pH regulation mode on the product spectrum. Two regulation modes were applied: in the first, pH was adjusted from 4.5 to 8.5 in progressive steps of 0.5 and in the second, covered the same pH range, but the pH was reset to 5.5 before each change. Acetate, butyrate, and ethanol were produced throughout all pH ranges, but there was a shift from butyrate at pH < 6.5 to ethanol at pH > 6.5, as well as a strong and consistent shift from hydrogen to formate as pH increased. Microbial analysis indicated that progressive pH resulted in dominance by Klebsiella, while reset pH resulted in a bias towards Clostridium spp., particularly at low pH, with higher variance in community between different pH levels. Reset pH was more responsive to changes in pH, and analysis of Gibbs free energy indicated that the reset pH experiments operated closer to thermodynamic equilibrium, particularly with respect to the formate/hydrogen balance. This may indicate that periodically resetting pH conforms better to thermodynamic expectations. PMID:27681895

Dispersed phase volume fraction, weak acids and Tween 80 in a model emulsion: Effect on the germination and growth of Bacillus weihenstephanensis KBAB4 spores.

PubMed

Léonard-Akkari, Lucie; Guégan, Stéphanie; Courand, Fabienne; Couvert, Olivier; Lepage, Jean-François; Rondeau-Mouro, Corinne; Desriac, Noémie; Mathot, Anne-Gabrielle; Leguérinel, Ivan; Coroller, Louis; Decourcelle, Nicolas

2018-07-01

In foodstuffs, physico-chemical interactions and/or physical constraints between spores, inhibitors and food components may exist. Thus, the objective of this study was to investigate such interactions using a model emulsion as a microbial medium in order to improve bacterial spore control with better knowledge of the interactions in the formulation. Emulsions were prepared with hexadecane mixed with nutrient broth using sonication and were stabilized by Tween 80 and Span 80. The hexadecane ratio was either 35% (v/v) or 50% (v/v) and each emulsion was studied in the presence of organic acid (acetic, lactic or hexanoic) at two pH levels (5.5 and 6). Self-diffusion coefficients of emulsion components and the organic acids were measured by Pulsed Field Gradient-Nuclear Magnetic Resonance (PFG-NMR). The inhibition effect on the spore germination and cell growth of Bacillus weihenstephanensis KBAB4 was characterized by the measure of the probability of growth using the most probable number methodology, and the measure of the time taken for the cells to germinate and grow using a single cell Bioscreen® method and using flow cytometry. The inhibition of spore germination and growth in the model emulsion depended on the dispersed phase volume fraction and the pH value. The effect of the dispersed phase volume fraction was due to a combination of (i) the lipophilicity of the biocide, hexanoic acid, that may have had an impact on the distribution of organic acid between hexadecane and the aqueous phases and (ii) the antimicrobial activity of the emulsifier Tween 80 detected at the acidic pH value. The interface phenomena seemed to have a major influence. Future work will focus on the exploration of these phenomena at the interface. Copyright © 2018 Elsevier Ltd. All rights reserved.

Modulation of the partition coefficient between octanol and buffer at pH 7.4 and pKa to achieve the optimum balance of blood clearance and volume of distribution for a series of tetrahydropyran histamine type 3 receptor antagonists.

PubMed

Hay, Tanya; Jones, Rhys; Beaumont, Kevin; Kemp, Mark

2009-09-01

The relationship between rat pharmacokinetics and physicochemical parameters [the partition coefficient between octanol and buffer at pH 7.4 (log D((7.4))) and pK(a)] was studied for a series of tetrahydropyran compounds. Sixteen compounds ranging in log D((7.4)) 0.1 to 1.8 were administered intravenously to rats, and the pharmacokinetic parameters were determined from blood concentration time curves. Across the series, a weak correlation was observed between log D((7.4)) and blood clearance, suggesting that log D((7.4)) values less than 0.5 were required to prevent clearance at hepatic blood flow. In terms of the volume of distribution (V(d)), the compounds fell into three distinct subseries characterized by the number of basic centers and differences in ionization of each basic center at physiological pH. These were referred to as the monobasic, weak second base, and strong second base subseries. All the compounds exhibited V(d) greater than body water, as would be expected from their lipophilic and basic nature. For a given clog P, the strong second base subseries showed higher V(d) than the weak second base subseries, which in turn exhibited higher values than the monobasic subseries. In addition, for the weak second base subseries, V(d) could be tuned by modulating the pK(a) of the second basic center. This relationship was rationalized in respect to the interactions of the ionizable centers with phospholipid heads in the cell membrane and/or lysosomal trapping. Compounds in the weak second base subseries showed optimal V(d), and when combined with a log D((7.4)) of 0.1, driving to moderate blood clearance, one compound showed the optimal pharmacokinetic profile.

Thin-film microextraction coupled to LC-ESI-MS/MS for determination of quaternary ammonium compounds in water samples.

PubMed

Boyacı, Ezel; Sparham, Chris; Pawliszyn, Janusz

2014-01-01

The dual nature of the quaternary ammonium compounds, having permanently charged hydrophilic quaternary ammonium heads and long-chain hydrophobic tails, makes the sample preparation step and analysis of these compounds challenging. A high-throughput method based on thin-film solid-phase microextraction (SPME) and liquid chromatography mass spectrometry was developed for simultaneous quantitative analysis of nine benzylic and aliphatic quaternary ammonium compounds. Chromatographic separation and detection of analytes were obtained in reverse-phase mode in 8 min using a triple quadrupole mass spectrometer. Hydrophilic lipophilic balance particle-coated blades were found to be the most suitable among the different coatings tested in terms of recoveries and carryover on the blades. For desorption solvents, 70/30, v/v (A/B) with 0.1 % formic acid (where A is 10 mM ammonium acetate in acetonitrile/water (95/5 , v/v) and B is 0.1 %  (v/v) formic acid in isopropyl alcohol) was shown to be the most efficient solvent for the desorption of the analytes from the SPME sorbent. The SPME method was optimised in terms of extraction, pH, and preconditioning, as well as extraction and desorption times. Optimum conditions were 45 min of extraction time and 15 min of desorption time, all with agitation. The extraction was found to be optimum in a range of pH 6.0 to 8.0, which is consistent with the natural pH of water samples. Wide linear dynamic ranges with the developed method were obtained for each compound, enabling the application of the method for a wide range of concentrations. The developed method was validated according to the Food and Drug Administration criteria. The proposed method is the first SPME-based approach describing the applicability of the high-throughput thin-film SPME in a 96-well system for analysis of such challenging compounds.

Application of Iron Oxide as a pH-dependent Indicator for Improving the Nutritional Quality

PubMed Central

2016-01-01

Acid food indicators can be used as pH indicators for evaluating the quality and freshness of fermented products during the full course of distribution. Iron oxide particles are hardly suspended in water, but partially or completely agglomerated. The agglomeration degree of the iron oxide particles depends on the pH. The pH-dependent particle agglomeration or dispersion can be useful for monitoring the acidity of food. The zeta potential of iron oxide showed a decreasing trend as the pH increased from 2 to 8, while the point of zero charge (PZC) was observed around at pH 6.0-7.0. These results suggested that the size of the iron oxide particles was affected by the change in pH levels. As a result, the particle sizes of iron oxide were smaller at lower pH than at neutral pH. In addition, agglomeration of the iron oxide particles increased as the pH increased from 2 to 7. In the time-dependent aggregation test, the average particle size was 730.4 nm and 1,340.3 nm at pH 2 and 7, respectively. These properties of iron oxide particles can be used to develop an ideal acid indicator for food pH and to monitor food quality, besides a colorant or nutrient for nutrition enhancement and sensory promotion in food industry. PMID:27482521

[Lipophilic yeasts of the genus Malassezia and skin diseases. I. Seborrhoeic dermatitis].

PubMed

Buchvald, D

2010-08-01

Recent technological advances have revived the interest in Malassezia yeasts and their clinical role, which has long been a matter of controversy because of their fastidious nature in vitro and relative difficulty in isolation, cultivation and identification. Lipophilic yeasts of the genus Malassezia form a part of normal microbial flora of healthy human (and animal) skin, but they also have been associated with several dermatological diseases, like seborrhoeic dermatitis and atopic dermatitis. Our understanding of the interactions between Malassezia and the host might provide new opportunities to better control these often chronically relapsing diseases.

Ring-substituted 4-hydroxy-1H-quinolin-2-ones: preparation and biological activity.

PubMed

Jampilek, Josef; Musiol, Robert; Pesko, Matus; Kralova, Katarina; Vejsova, Marcela; Carroll, James; Coffey, Aidan; Finster, Jacek; Tabak, Dominik; Niedbala, Halina; Kozik, Violetta; Polanski, Jaroslaw; Csollei, Jozef; Dohnal, Jiri

2009-03-13

In the study, a series of twelve ring-substituted 4-hydroxy-1H-quinolin-2-one derivatives were prepared. The procedures for synthesis of the compounds are presented. The compounds were analyzed using RP-HPLC to determine lipophilicity and tested for their photosynthesis-inhibiting activity using spinach (Spinacia oleracea L.) chloroplasts. All the synthesized compounds were also evaluated for antifungal activity using in vitro screening with eight fungal strains. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds are discussed, as well as their structure-activity relationships (SAR).

Safer staining method for acid fast bacilli.

PubMed Central

Ellis, R C; Zabrowarny, L A

1993-01-01

To develop a method for staining acid fast bacilli which excluded highly toxic phenol from the staining solution. A lipophilic agent, a liquid organic detergent, LOC High Studs, distributed by Amway, was substituted. The acid fast bacilli stained red; nuclei, cytoplasm, and cytoplasmic elements stained blue on a clear background. These results compare very favourably with acid fast bacilli stained by the traditional method. Detergents are efficient lipophilic agents and safer to handle than phenol. The method described here stains acid fast bacilli as efficiently as traditional carbol fuchsin methods. LOC High Suds is considerably cheaper than phenol. Images PMID:7687254

Safer staining method for acid fast bacilli.

PubMed

Ellis, R C; Zabrowarny, L A

1993-06-01

To develop a method for staining acid fast bacilli which excluded highly toxic phenol from the staining solution. A lipophilic agent, a liquid organic detergent, LOC High Studs, distributed by Amway, was substituted. The acid fast bacilli stained red; nuclei, cytoplasm, and cytoplasmic elements stained blue on a clear background. These results compare very favourably with acid fast bacilli stained by the traditional method. Detergents are efficient lipophilic agents and safer to handle than phenol. The method described here stains acid fast bacilli as efficiently as traditional carbol fuchsin methods. LOC High Suds is considerably cheaper than phenol.

Lead optimization using matched molecular pairs: inclusion of contextual information for enhanced prediction of HERG inhibition, solubility, and lipophilicity.

PubMed

Papadatos, George; Alkarouri, Muhammad; Gillet, Valerie J; Willett, Peter; Kadirkamanathan, Visakan; Luscombe, Christopher N; Bravi, Gianpaolo; Richmond, Nicola J; Pickett, Stephen D; Hussain, Jameed; Pritchard, John M; Cooper, Anthony W J; Macdonald, Simon J F

2010-10-25

Previous studies of the analysis of molecular matched pairs (MMPs) have often assumed that the effect of a substructural transformation on a molecular property is independent of the context (i.e., the local structural environment in which that transformation occurs). Experiments with large sets of hERG, solubility, and lipophilicity data demonstrate that the inclusion of contextual information can enhance the predictive power of MMP analyses, with significant trends (both positive and negative) being identified that are not apparent when using conventional, context-independent approaches.

Diversity of compounds in femoral secretions of Galápagos iguanas (genera: Amblyrhynchus and Conolophus), and their potential role in sexual communication in lek-mating marine iguanas (Amblyrhynchus cristatus).

PubMed

Ibáñez, Alejandro; Menke, Markus; Quezada, Galo; Jiménez-Uzcátegui, Gustavo; Schulz, Stefan; Steinfartz, Sebastian

2017-01-01

Chemical signals are widely used in the animal kingdom, enabling communication in various social contexts, including mate selection and the establishment of dominance. Femoral glands, which produce and release waxy secretions into the environment, are organs of central importance in lizard chemical communication. The Galápagos marine iguana ( Amblyrhynchus cristatus ) is a squamate reptile with a lek-mating system. Although the lekking behaviour of marine iguanas has been well-studied, their potential for sexual communication via chemical cues has not yet been investigated. Here we describe the diversity of the lipophilic fraction of males' femoral gland secretions among 11 island populations of marine iguanas, and compare it with the composition of its sister species, the Galápagos land iguana ( Conolophus subcristatus ). We also conducted behavioural observations in marine iguana territorial males in order to explore the possible function of these substances in the context of male dominance in leks. Femoral secretions were analysed by gas chromatography coupled to mass spectrometry (GC-MS), and chromatography with a flame ionisation detector (GC-FID) in order to characterise the lipophilic composition. To understand the potential role of femoral secretions in marine iguana intraspecific communication, territorial males were sampled for their femoral glands and monitored to record their head bob rate-a territorial display behaviour in males-as well as the number of females present in their leks. We found that the gland secretions were composed of ten saturated and unsaturated carboxylic acids ranging in chain length between C 16 and C 24 , as well as three sterols. Cholesterol was the main compound found. Intriguingly, land iguanas have a higher diversity of lipophilic compounds, with structural group of lipids (i.e. aldehydes) entirely absent in marine iguanas; overall the chemical signals of both species were strongly differentiated. Lipid profiles also differed among populations of marine iguanas from different islands, with some islands demonstrating a high diversity of lipophilic compounds (i.e. full spectra of compounds), and others lacking one or more compounds. Among the compounds most frequently found missing were 11- and 13-eicosenoic acids. Gland secretions of males with a better body condition and with a higher dominance status (i.e. those accompanied by females and with higher head bob display) were proportionately richer in C 20 -unsaturated fatty acids (11-eicosenoic acid). Land and marine iguanas strongly diverged in their chemical composition of the femoral glands likely due to ecological differences between both species. Despite that marine iguana populations varied in their femoral gland composition that was not related to their genetic structure. Our results indicated that 11-eicosenoic acid may play an important role in intraspecific chemical communication in marine iguanas.

Natural variance in pH as a complication in detecting acidification of lakes

USGS Publications Warehouse

Turk, J.T.

1988-01-01

Natural variance in the pH of three dilute lakes in the Flat Tops Wilderness Area, Colorado, complicates the detection of acidification. Variations in pH during July-September of 1983 were: 0.95 (Ned Wilson Lake), 1.36 (Upper Island Lake), and 1.53 (Oyster Lake). Mean diurnal variations in pH during 1983 were: 0.37 (Ned Wilson Lake), 0.54 (Upper Island Lake), and 0.39 (Oyster Lake). Replicate pH measurements indicate that pH can be measured with a mean variance due to measurement error of ?? 0.005. Regression analysis indicates that samples collected on the same day of different years may differ because of time of day and percentage of cloud cover. Differences in wind duration and intensity and primary productivity also may cause the pH to differ between years. Such differences can be either random or systematic. Comparisons of pH among 3 yr of data from Ned Wilson Lake indicate that natural variations in pH are much larger than variations in Colorado Lakes previously attributed to acidification by precipitation.

Pharmacological activities of Vitex agnus-castus extracts in vitro.

PubMed

Meier, B; Berger, D; Hoberg, E; Sticher, O; Schaffner, W

2000-10-01

The pharmacological effects of ethanolic Vitex agnus-castus fruit-extracts (especially Ze 440) and various extract fractions of different polarities were evaluated both by radioligand binding studies and by superfusion experiments. A relative potent binding inhibition was observed for dopamine D2 and opioid (micro and kappa subtype) receptors with IC50 values of the native extract between 20 and 70 mg/mL. Binding, neither to the histamine H1, benzodiazepine and OFQ receptor, nor to the binding-site of the serotonin (5-HT) transporter, was significantly inhibited. The lipophilic fractions contained the diterpenes rotun-difuran and 6beta,7beta-diacetoxy-13-hydroxy-labda-8,14-dien . They exhibited inhibitory actions on dopamine D2 receptor binding. While binding inhibition to mu and kappa opioid receptors was most pronounced in lipophilic fractions, binding to delta opioid receptors was inhibited mainly by a aqueous fraction. Standardised Ze 440 extracts of different batches were of constant pharmacological quality according to their potential to inhibit the binding to D2 receptors. In superfusion experiments, the aqueous fraction of a methanolic extract inhibited the release of acetylcholine in a concentration-dependent manner. In addition, the potent D2 receptor antagonist spiperone antagonised the effect of the extract suggesting a dopaminergic action mediated by D2 receptor activation. Our results indicate a dopaminergic effect of Vitex agnus-castus extracts and suggest additional pharmacological actions via opioid receptors.

Tissue-specific concentrations and patterns of perfluoroalkyl carboxylates and sulfonates in East Greenland polar bears.

PubMed

Greaves, Alana K; Letcher, Robert J; Sonne, Christian; Dietz, Rune; Born, Erik W

2012-11-06

Several perfluoroalkyl carboxylates (PFCAs) and perfluoroalkyl sulfonates (PFSAs) of varying chain length are bioaccumulative in biota. However, wildlife reports have focused on liver and with very little examination of other tissues, and thus there is a limited understanding of their distribution and potential effects in the mammalian body. In the present study, the comparative accumulation of C(6) to C(15) PFCAs, C(4), C(6), C(8) and C(10) PFSAs, and select precursors were examined in the liver, blood, muscle, adipose, and brain of 20 polar bears (Ursus maritimus) from Scoresby Sound, Central East Greenland. Overall, PFSA and PFCA concentrations were highest in liver followed by blood > brain > muscle ≈ adipose. Liver and blood samples contained proportionally more of the shorter/medium chain length (C(6) to C(11)) PFCAs, whereas adipose and brain samples were dominated by longer chain (C(13) to C(15)) PFCAs. PFCAs with lower lipophilicities accumulated more in the liver, whereas the brain accumulated PFCAs with higher lipophilicities. The concentration ratios (±SE) between perfluorooctane sulfonate and its precursor perfluorooctane sulfonamide varied among tissues from 9 (±1):1 (muscle) to 36 (±7):1 (liver). PFCA and PFSA patterns in polar bears indicate that the pharmacokinetics of these compounds are to some extent tissue-specific, and are the result of several factors that may include differing protein interactions throughout the body.

Synthesis and Anti-cancer Activity of Novel Thiazolidinone Analogs of 6-Aminoflavone.

PubMed

Moorkoth, Sudheer

2015-01-01

Novel heterocyclic analogs were synthesized by combining a flavone nucleus and thiazolidinone ring in an effort to potentiate the existing anti-cancer activity of flavone. The syntheses of 6-aminoflavone, 6-amino-3-methoxyflavone, 6-amino-3-methoxy-3',4'-dimethxyflavone and their corresponding thiazolidinone analogs were performed. Fifteen novel analogs were synthesized and evaluated for their anti-cancer activity using cell-based assay techniques and in vivo testing. As expected, the analogs improved cytotoxicity and were shown to increase the life span of cancer-bearing mice. Cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays in HeLa, MDA-MB-435, and Vero cell lines. In vivo evaluation of anti-cancer activity performed in albino mice bearing Dalton's ascites carcinoma showed that the new analogs enhanced life span and prevented increases in body weight owing to tumor volumes. Moreover, cell-cycle analysis and Hoechst staining analysis proved the apoptotic potential of these analogs. Preliminary pharmacokinetic evaluation was carried out on the synthesized compounds to determine the lipophilicity and pKa. Lipophilicity was determined using high-performance liquid chromatography and the results showed a direct correlation between the observed anti-cancer activity and log P value, while pKa values indicated the ionizing range which is a prediction tool for solubility and permeability.

Metabolic concentration of lipid soluble organochlorine burdens in the blubber of southern hemisphere humpback whales through migration and fasting.

PubMed

Bengtson Nash, Susan M; Waugh, Courtney A; Schlabach, Martin

2013-08-20

Southern hemisphere humpback whales undertake the longest migrations and associated periods of fasting of any mammal. Fluctuations in lipid energy stores are known to profoundly affect the toxicokinetics of lipophilic organochlorine compound (OC) burdens. Results from blubber biopsy sampling of adult, male humpback whales at two time points of the annual migration journey revealed dramatic concentration effects for the majority of OC compounds. The observed concentration effect was, however, not linear with measured average blubber lipid loss indicating significant redistribution of OCs and hence the importance of alternate lipid depots for meeting the energetic demands of the migration journey. Applying lipophilic OC burdens as novel tracers of whole-body lipid dynamics, the observed average concentration index suggests an average individual weight loss of 13% over 4 months of the migration journey. This value is based upon lipid derived energy and is in good agreement with previous weight prediction formulas. Notably, however, these estimates may greatly underestimate individual weight loss if significant protein catabolism occurs. Biomagnification factors between migrating southern hemisphere humpback whales and their principal prey item, Antarctic krill, closely resembled those of baleen whales feeding on herbivorous zooplankton in the Arctic. This study emphasizes the importance of considering prolonged periods of food deprivation when assessing chemical risks posed to wildlife. This is of particular importance for Polar biota adapted to extremes in ecosystem productivity.

Toxicokinetics and effects of PCBs in Arctic fish: a review of studies on Arctic charr

USGS Publications Warehouse

Jorgensen, EH; Vijayan, M.N.; Killie, J.-E.A.; Aluru, N.; Aas-Hansen, O.; Maule, A.

2006-01-01

In a series of environmentally realistic laboratory experiments, toxicokinetics and effects of polychlorinated biphenyls (PCBs) were studied in the Arctic charr (Salvelinus alpinus). Winter fasting and emaciation, which are common among Arctic charr living in high latitudes, resulted in a redistribution of the lipophilic PCBs from lipid-storing tissue such as the muscle, to vital organs that must be considered sensitive toward PCB (liver and brain). This redistribution was accompanied by a significant potentiation of the hepatic cytochrome P-450 (CYP) 1A biomarker response, from low activities in October (within those measured in uncontaminated charr) to a high, probably maximum, induction in May. Performance studies demonstrated a clear effect of environmentally realistic PCB levels on endocrine mechanisms, immune function, and seawater preadaptation (smoltification) in charr that had been feed deprived for several months after contamination with Aroclor 1254, whereas a high PCB dose exerted only minor, if any, effects in charr that had been fed after contamination. These results demonstrate that emaciation results in decreased dose-response relationships in fish, and indicate that arctic animals undergoing seasonal cycles of "fattening" and emaciation may be extra sensitive toward persistent, lipophilic organochlorines. Pilot studies on Arctic charr from Bjørnøya Island revealed marked CYP1A biomarker responses and an upregulation of genes involved in cellular homeostatic mechanisms in charr from Lake Ellasjøen (high PCB levels).

A novel optical probe for pH sensing in gastro-esophageal apparatus

NASA Astrophysics Data System (ADS)

Baldini, F.; Ghini, G.; Giannetti, A.; Senesi, F.; Trono, C.

2011-03-01

Monitoring gastric pH for long periods, usually 24 h, may be essential in analyzing the physiological pattern of acidity, in obtaining information on changes in activity during peptic ulcer disease, and in assessing the effect of antisecretory drugs. Gastro-esophageal reflux, which causes a pH decrease in the esophagus content from pH 7 even down to pH 2, can determine esophagitis with possible strictures and Barrett's esophagus. One of the difficulties of the optical measurement of pH in the gastro-esophageal apparatus lies in the required extended working range from 1 to 8 pH units. The present paper deals with a novel optical pH sensor, using methyl red as optical pH indicator. Contrary to all acidbase indicators characterized by working ranges limited to 2-3 pH units, methyl red, after its covalent immobilization on controlled pore glass (CPG), is characterized by a wide working range which fits with the clinical requirements. The novel probe design here described is suitable for gastro-esophageal applications and allows the optimization of the performances of the CPG with the immobilised indicator. This leads to a very simple configuration characterized by a very fast response time.

Effects of imposed acid-base derangement on the cardiovascular effects and pharmacokinetics of bupivacaine and thiopental.

PubMed

Mather, Laurence E; Ladd, Leigh A; Copeland, Susan E; Chang, Dennis H-T

2004-06-01

By changing physicochemical properties such as effective lipophilicity, changes in blood pH could alter the distribution, elimination, and effects of weakly ionizing drugs. The authors examined the outcome of imposed acid-base derangement on cardiovascular effects and myocardial and whole body pharmacokinetics of bupivacaine, a weak base, and thiopental, a weak acid. Intravenous infusions of rac-bupivacaine HCl (37.5 mg) or rac-thiopental sodium (250 mg, subanesthetic dose) were administered over 3 min to previously instrumented conscious ewes with normal blood pH, acidemia imposed by lactic acid infusion, or alkalemia imposed by bicarbonate infusion. Hemodynamic and electrocardiographic effects were recorded; arterial and coronary sinus drug blood concentrations were analyzed by chiral high-performance liquid chromatography. Bupivacaine decreased myocardial contractility, coronary perfusion, heart rate, and cardiac output; however, cardiac output and stroke volume were not as affected by bupivacaine with acidemia. Thiopental decreased myocardial contractility and stroke volume and increased heart rate; acidemia enhanced the tachycardia and produced a greater decrease in stroke volume than with alkalemia. Taken as a whole, the cardiovascular changes were not systematically modified by acid-base derangement. Overall, the tissue distribution of bupivacaine was favored by alkalemia, but thiopental pharmacokinetics were essentially unaffected by acid-base derangement. Acid-base derangement did not influence the kinetics of either drug enantioselectively. At the doses used, the hemodynamic and electrocardiographic effects of bupivacaine and thiopental were not systematically modified by acid-base derangement, nor were there changes in regional or whole body pharmacokinetics of either drug that were clearly related to acid-base status.

Six post-implantation lethal knockouts of genes for lipophilic MAPK pathway proteins are expressed in preimplantation mouse embryos and trophoblast stem cells.

PubMed

Xie, Yufen; Wang, Yingchun; Sun, Tong; Wang, Fangfei; Trostinskaia, Anna; Puscheck, Elizabeth; Rappolee, Daniel A

2005-05-01

Mitogen-activated protein kinase (MAPK) signaling pathways play an important role in controlling embryonic proliferation and differentiation. It has been demonstrated that sequential lipophilic signal transduction mediators that participate in the MAPK pathway are null post-implantation lethal. It is not clear why the lethality of these null mutants arises after implantation and not before. One hypothesis is that the gene product of these post-implantation lethal null mutants are not present before implantation in normal embryos and do not have function until after implantation. To test this hypothesis, we selected a set of lipophilic genes mediating MAPK signal transduction pathways whose null mutants result in early peri-implantation or placental lethality. These included FRS2alpha, GAB1, GRB2, SOS1, Raf-B, and Raf1. Products of these selected genes were detected and their locations and functions indicated by indirect immunocytochemistry and Western blotting for proteins and RT-polymerase chain reaction (PCR) for mRNA transcription. We report here that all six signal mediators are detected at the protein level in preimplantation mouse embryo, placental trophoblasts, and in cultured trophoblast stem cells (TSC). Proteins are all detected in E3.5 embryos at a time when the first known mitogenic intercellular communication has been documented. mRNA transcripts of two post-implantation null mutant genes are expressed in mouse preimplantation embryos and unfertilized eggs. These mRNA transcripts were detected as maternal mRNA in unfertilized eggs that could delay the lethality of null mutants. All of the proteins were detected in the cytoplasm or in the cell membrane. This study of spatial and temporal expression revealed that all of these six null mutants post-implantation genes in MAPK pathway are expressed and, where tested, phosphorylated/activated proteins are detected in the blastocyst. Studies on RNA expression using RT-PCR suggest that maternal RNA could play an important role in delaying the presence of the lethal phenotype of null mutations. Copyright (c) 2005 Wiley-Liss, Inc.

Optimized nano-transfersomal films for enhanced sildenafil citrate transdermal delivery: ex vivo and in vivo evaluation

PubMed Central

Badr-Eldin, Shaimaa M; Ahmed, Osamaa AA

2016-01-01

Sildenafil citrate (SLD) is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor used for the oral treatment of erectile dysfunction and, more recently, for other indications, including pulmonary hypertension. The challenges facing the oral administration of the drug include poor bioavailability and short duration of action that requires frequent administration. Thus, the objective of this work is to formulate optimized SLD nano-transfersomal transdermal films with enhanced and controlled permeation aiming at surmounting the previously mentioned challenges and hence improving the drug bioavailability. SLD nano-transfersomes were prepared using modified lipid hydration technique. Central composite design was applied for the optimization of SLD nano-transfersomes with minimized vesicular size. The independent variables studied were drug-to-phospholipid molar ratio, surfactant hydrophilic lipophilic balance, and hydration medium pH. The optimized SLD nano-transfersomes were developed and evaluated for vesicular size and morphology and then incorporated into hydroxypropyl methyl cellulose transdermal films. The optimized transfersomes were unilamellar and spherical in shape with vesicular size of 130 nm. The optimized SLD nano-transfersomal films exhibited enhanced ex vivo permeation parameters with controlled profile compared to SLD control films. Furthermore, enhanced bioavailability and extended absorption were demonstrated by SLD nano-transfersomal films as reflected by their significantly higher maximum plasma concentration (Cmax) and area under the curve and longer time to maxi mum plasma concentration (Tmax) compared to control films. These results highlighted the potentiality of optimized SLD nano-transfersomal films to enhance the transdermal permeation and the bioavailability of the drug with the possible consequence of reducing the dose and administration frequency. PMID:27103786

Optimized nano-transfersomal films for enhanced sildenafil citrate transdermal delivery: ex vivo and in vivo evaluation.

PubMed

Badr-Eldin, Shaimaa M; Ahmed, Osamaa Aa

2016-01-01

Sildenafil citrate (SLD) is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor used for the oral treatment of erectile dysfunction and, more recently, for other indications, including pulmonary hypertension. The challenges facing the oral administration of the drug include poor bioavailability and short duration of action that requires frequent administration. Thus, the objective of this work is to formulate optimized SLD nano-transfersomal transdermal films with enhanced and controlled permeation aiming at surmounting the previously mentioned challenges and hence improving the drug bioavailability. SLD nano-transfersomes were prepared using modified lipid hydration technique. Central composite design was applied for the optimization of SLD nano-transfersomes with minimized vesicular size. The independent variables studied were drug-to-phospholipid molar ratio, surfactant hydrophilic lipophilic balance, and hydration medium pH. The optimized SLD nano-transfersomes were developed and evaluated for vesicular size and morphology and then incorporated into hydroxypropyl methyl cellulose transdermal films. The optimized transfersomes were unilamellar and spherical in shape with vesicular size of 130 nm. The optimized SLD nano-transfersomal films exhibited enhanced ex vivo permeation parameters with controlled profile compared to SLD control films. Furthermore, enhanced bioavailability and extended absorption were demonstrated by SLD nano-transfersomal films as reflected by their significantly higher maximum plasma concentration (C max) and area under the curve and longer time to maxi mum plasma concentration (T max) compared to control films. These results highlighted the potentiality of optimized SLD nano-transfersomal films to enhance the transdermal permeation and the bioavailability of the drug with the possible consequence of reducing the dose and administration frequency.

Diffusive gradients in thin-films (DGT) for in situ sampling of selected endocrine disrupting chemicals (EDCs) in waters.

PubMed

Chen, Wei; Pan, Suhong; Cheng, Hao; Sweetman, Andrew J; Zhang, Hao; Jones, Kevin C

2018-06-15

A passive water sampler based on the diffusive gradients in thin-films (DGT) technique was developed and tested for 3 groups of endocrine disrupting chemicals (EDCs, including oestrogens, alkyl-phenols and bisphenols). Three different resins (hydrophilic-lipophilic-balanced (HLB), XAD18 and Strata-XL-A (SXLA)) were investigated for their suitability as the binding phase for DGT devices. Laboratory tests across a range of pH (3.5-9.5), ionic strength (0.001-0.5 M) and dissolved organic matter concentration (0-20 mg L -1 ) showed HLB and XAD18-DGT devices were more stable compared to SXLA-DGT. HLB-DGT and XAD18-DGT accumulated test chemicals with time consistent with theoretical predictions, while SXLA-DGT accumulated reduced amounts of chemical. DGT performance was also compared in field deployments up to 28 days, alongside conventional active sampling at a wastewater treatment plant. Uptake was linear to the samplers over 18 days, and then began to plateau/decline, indicating the maximum deployment time in those conditions. Concentrations provided by the DGT samplers compared well with those provided by auto-samplers. DGT integrated concentrations over the deployment period in a way that grab-sampling cannot. The advantages of the DGT sampler over active sampling include: low cost, ease of simultaneous multi-site deployment, in situ analyte pre-concentration and reduction of matrix interferences compared with conventional methods. Compared to other passive sampler designs, DGT uptake is independent of flow rate and therefore allows direct derivation of field concentrations from measured compound diffusion coefficients. This passive DGT sampler therefore constitutes a viable and attractive alternative to conventional grab and active water sampling for routine monitoring of selected EDCs. Copyright © 2018 Elsevier Ltd. All rights reserved.

Application of perfluorinated acids as ion-pairing reagents for reversed-phase chromatography and retention-hydrophobicity relationships studies of selected beta-blockers.

PubMed

Flieger, J

2010-01-22

The addition of the homologous series of perfluorinated acids-trifluoroacetic acid (TFAA), pentafluoropropionic acid (PFPA), heptafluorobutyric acid (HFBA) to mobile phases for reversed-phase high-performance liquid chromatography (RP-HPLC) of beta-blockers was tested. Acidic modifiers were responsible for acidification of mobile phase (pH 3) ensuring the protonation of the beta-blockers and further ion pairs creation. The effect of the type and concentration of mobile phase additives on retention parameters, the efficiency of the peaks, their symmetry and separation selectivity of the beta-blockers mixture were all studied. It appeared that at increasing acid concentration, the retention factor, for all compounds investigated, increased to varying degrees. It should be stressed that the presence of acids more significantly affected the retention of the most hydrophobic beta-blockers. Differences in hydrophobicity of drugs can be maximized through variation of the hydrophobicity of additives. Thus, the relative increase in the retention depends on either concentration and hydrophobicity of the anionic mobile phase additive or hydrophobicity of analytes. According to QSRR (quantitative structure retention relationship) methodology, chromatographic lipophilicity parameters: isocratic log k and log k(w) values (extrapolated retention to pure water) were correlated with the molecular (log P(o/w)) and apparent (log P(app)) octanol-water partition coefficients obtained experimentally by countercurrent chromatography (CCC) or predicted by Pallas software. The obtained, satisfactory retention-hydrophobicity correlations indicate that, in the case of the basic drugs examined in RP-HPLC systems modified with perfluorinated acids, the retention is mainly governed by their hydrophobicity. Copyright 2009 Elsevier B.V. All rights reserved.

Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer.

PubMed

Vogel, Tilley Jenkins; Goodman, Marc T; Li, Andrew J; Jeon, Christie Y

2017-08-01

Observational studies suggest that statin therapy for cardio-protection is associated with improved survival in cancer patients. We sought to evaluate the impact of statin treatment on ovarian cancer survival in a nationally representative elderly population. The linked Surveillance, Epidemiology, and End Results (SEER) registries and Medicare claims data on patients diagnosed with epithelial ovarian cancer in 2007-2009 were used to extract data on statin prescription fills, population characteristics, primary treatment, comorbidity and survival. Cox regression models were used to examine the association between statin treatment and overall survival. Among the 1431 ovarian cancer patients who underwent surgical resection, 609 (42.6%) filled prescriptions for statin. The majority of statin-users (89%) were prescribed a lipophilic formulation. Mean overall survival among statin-users was 32.3months compared to 28.8months for non-users (p<0.0001). A 34% reduction in death was associated with statin therapy, independent of age, race, neighborhood median household income, stage, platinum therapy and comorbid conditions (HR=0.66, 95% CI 0.55-0.81). Improved overall survival with statin use was observed for both serous (HR=0.69, 95% CI 0.54-0.87) and non-serous (HR=0.63, 95% CI 0.44-0.90) histologies. When statin treatment was categorized by lipophilicity and intensity, a significant survival benefit was limited to lipophilic statin users and those who took statins of moderate intensity. This SEER-Medicare analysis demonstrates improvement in overall survival with lipophilic statin use after surgery in elderly patients with epithelial ovarian cancer. A clinical trial to evaluate the impact of statin treatment in ovarian cancer survival is warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

Fatty Acid Binding Proteins Expressed at the Human Blood-Brain Barrier Bind Drugs in an Isoform-Specific Manner.

PubMed

Lee, Gordon S; Kappler, Katharina; Porter, Christopher J H; Scanlon, Martin J; Nicolazzo, Joseph A

2015-10-01

To examine the expression of fatty acid binding proteins (FABPs) at the human blood-brain barrier (BBB) and to assess their ability to bind lipophilic drugs. mRNA and protein expression of FABP subtypes in immortalized human brain endothelial (hCMEC/D3) cells were examined by RT-qPCR and Western blot, respectively. FABPs that were found in hCMEC/D3 cells (hFABPs) were recombinantly expressed and purified from Escherichia coli C41(DE3) cells. Drug binding to these hFABPs was assessed using a fluorescence assay, which measured the ability of a panel of lipophilic drugs to displace the fluorescent probe compound 1-anilinonaphthalene-8-sulfonic acid (ANS). hFABP3, 4 and 5 were expressed in hCMEC/D3 cells at the mRNA and protein level. The competitive ANS displacement assay demonstrated that, in general, glitazones preferentially bound to hFABP5 (Ki: 1.0-28 μM) and fibrates and fenamates preferentially bound to hFABP4 (Ki: 0.100-17 μM). In general, lipophilic drugs appeared to show weaker affinities for hFABP3 relative to hFABP4 and hFABP5. No clear correlation was observed between the molecular structure or physicochemical properties of the drugs and their ability to displace ANS from hFABP3, 4 and 5. hFABP3, 4 and 5 are expressed at the human BBB and bind differentially to a diverse range of lipophilic drugs. The unique expression and binding patterns of hFABPs at the BBB may therefore influence drug disposition into the brain.

Ultra-trace level determination of diquat and paraquat residues in surface and drinking water using ion-pair liquid chromatography with tandem mass spectrometry: a comparison of direct injection and solid-phase extraction methods.

PubMed

Oh, Jin-Aa; Lee, Jun-Bae; Lee, Soo-Hyung; Shin, Ho-Sang

2014-10-01

Direct injection and solid-phase extraction methods for the determination of diquat and paraquat in surface and drinking water were developed using liquid chromatography with tandem mass spectrometry. The signal intensities of analytes based on six ion-pairing reagents were compared with each other, and 12.5 mM nonafluoropentanoic acid was selected as the best suited amongst them. A clean-up method was developed using Oasis hydrophilic-lipophilic balance; this was compared to the direct injection method, with respect to limits of detection, interference, precision, and accuracy. Limits of quantification of diquat and paraquat were 0.03 and 0.01 μg/L using the direct injection method, and 0.002 and 0.001 μg/L using the hydrophilic-lipophilic balance method. When the hydrophilic-lipophilic balance method was used to analyze target compounds in 114 surface water and 30 drinking water samples, paraquat and diquat were detected within a concentration range of 0.001-0.12 and 0.002-0.038 μg/L in surface water, respectively. When the direct injection method was used to analyze target compounds in the same samples, the detected concentrations of paraquat and diquat were within 25% in samples being >0.015 μg/L using the hydrophilic-lipophilic balance method. The liquid chromatography with tandem mass spectrometry method using direct injection can thus be used for routine monitoring of paraquat and diquat in surface and drinking water. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Effects of sub-micro emulsion composition on cellular disposition of incorporated lipophilic drug].

PubMed

Sun, Xiao-Yi; Xiang, Zhi-Qiang; Wu, Shuo; Lv, Yuan-Yuan; Liang, Wen-Quan

2013-09-01

To investigate the effects of sub-micro emulsion composition on cellular uptake and disposition of incorporated lipophilic drug. Sub-micro emulsions containing 10 % oil, 1.2 % lecithin and 2.25 % glycerol were prepared, and the fluorescent agent coumarin 6 was used as a model drug. The effects of oil types, co-surfactants and cationic lipid on uptake and elimination kinetics of 6-coumarin in HeLa cells were studied. The uptake mechanism of sub-micro emulsions was further investigated. Oil type and Tweens had no influence on the cellular uptake. Modifications of surfactants with Span series increased the cellular influx, among which Span 20 with hydrophilic-lipophilic balance (HLB) value of 8.6 was the best enhancer. The intracellular drug level reached up to (46.09 ± 1.98)ng/μg protein which had significant difference with control group [(38.54 ± 0.34)ng/μg protein]. The positively charged emulsions significantly increased the uptake rate constant and elimination rate constant which were 4 times and 1.5 times of those in anionic groups, respectively. The uptake enhancement was also observed in cationic emulsions, cellular concentrations at plateau were (42.73 ± 0.84)ng/μg protein, which was about 3 times of that in anionic emulsions [(15.71 ± 0.74)ng/μg protein], when extracellular drug concentration kept at 100 ng/ml. Cationic emulsions delivered the payload mainly by direct drug transfer to contacted cells, while the negative ones depended on both drug passive diffusion and clathrin-mediated endocytosis of drug containing oil droplets which accounted for 20% of the intracellular drug. Interfacial characteristic of sub-micro emulsions such as co-surfactants HLB as well as zeta potentials can influence lipophilic drug both in cellular uptake and elimination.

Factors affecting drug encapsulation and stability of lipid-polymer hybrid nanoparticles.

PubMed

Cheow, Wean Sin; Hadinoto, Kunn

2011-07-01

Lipid-polymer hybrid nanoparticles are polymeric nanoparticles enveloped by lipid layers that combine the highly biocompatible nature of lipids with the structural integrity afforded by polymeric nanoparticles. Recognizing them as attractive drug delivery vehicles, antibiotics are encapsulated in the present work into hybrid nanoparticles intended for lung biofilm infection therapy. Modified emulsification-solvent-evaporation methods using lipid as surfactant are employed to prepare the hybrid nanoparticles. Biodegradable poly (lactic-co-glycolic acid) and phosphatidylcholine are used as the polymer and lipid models, respectively. Three fluoroquinolone antibiotics (i.e. levofloxacin, ciprofloxacin, and ofloxacin), which vary in their ionicity, lipophilicity, and aqueous solubility, are used. The hybrid nanoparticles are examined in terms of their drug encapsulation efficiency, drug loading, stability, and in vitro drug release profile. Compared to polymeric nanoparticles prepared using non-lipid surfactants, hybrid nanoparticles in general are larger and exhibit higher drug loading, except for the ciprofloxacin-encapsulated nanoparticles. Hybrid nanoparticles, however, are unstable in salt solutions, but the stability can be conferred by adding TPGS into the formulation. Drug-lipid ionic interactions and drug lipophilicity play important roles in the hybrid nanoparticle preparation. First, interactions between oppositely charged lipid and antibiotic (i.e. ciprofloxacin) during preparation cause failed nanoparticle formation. Charge reversal of the lipid facilitated by adding counterionic surfactants (e.g. stearylamine) must be performed before drug encapsulation can take place. Second, drug loading and the release profile are strongly influenced by drug lipophilicity, where more lipophilic drug (i.e. levofloxacin) exhibit a higher drug loading and a sustained release profile attributed to the interaction with the lipid coat. Copyright © 2011 Elsevier B.V. All rights reserved.

Radiochemical studies of 99mTc complexes of modified cysteine ligands and bifunctional chelating agents.

PubMed

Pillai, M R; Kothari, K; Banerjee, S; Samuel, G; Suresh, M; Sarma, H D; Jurisson, S

1999-07-01

The synthesis of four novel ligands using the amino-acid cysteine and its ethyl carboxylate derivative is described. The synthetic method involves a two-step procedure, wherein the intermediate Schiff base formed by the condensation of the amino group of the cysteine substrate and salicylaldehyde is reduced to give the target ligands. The intermediates and the final products were characterized by high resolution nuclear magnetic resonance spectroscopy. Complexation studies of the ligands with 99mTc were optimized using stannous tartrate as the reducing agent under varying reaction conditions. The complexes were characterized using standard quality control techniques such as thin layer chromatography, paper electrophoresis, and paper chromatography. Lipophilicities of the complexes were estimated by solvent extraction into chloroform. Substantial changes in net charge and lipophilicity of the 99mTc complexes were observed on substituting the carboxylic acid functionality in ligands I and II with the ethyl carboxylate groups (ligands II and IV). All the ligands formed 99mTc complexes in high yield. Whereas the complexes with ligands I and II were observed to be hydrophilic in nature and not extractable into CHCl3, ligands III and IV resulted in neutral and lipophilic 99mTc complexes. The 99mTc complex with ligand II was not stable and on storage formed a hydrophilic and nonextractable species. The biodistribution of the complexes of ligands I and II showed that they cleared predominantly through the kidneys, whereas the complexes with ligands III and IV were excreted primarily through the hepatobiliary system. No significant brain uptake was observed with the 99mTc complexes with ligands III and IV despite their favorable properties of neutrality, lipophilicity, and conversion into a hydrophilic species. These ligands offer potential for use as bifunctional chelating agents.

Lipophilic and hydrophilic antioxidant capacities of common foods in the United States.

PubMed

Wu, Xianli; Beecher, Gary R; Holden, Joanne M; Haytowitz, David B; Gebhardt, Susan E; Prior, Ronald L

2004-06-16

Both lipophilic and hydrophilic antioxidant capacities were determined using the oxygen radical absorbance capacity (ORAC(FL)) assay with fluorescein as the fluorescent probe and 2,2'-azobis(2-amidinopropane) dihydrochloride as a peroxyl radical generator on over 100 different kinds of foods, including fruits, vegetables, nuts, dried fruits, spices, cereals, infant, and other foods. Most of the foods were collected from four different regions and during two different seasons in U.S. markets. Total phenolics of each sample were also measured using the Folin-Ciocalteu reagent. Hydrophilic ORAC(FL) values (H-ORAC(FL)) ranged from 0.87 to 2641 micromol of Trolox equivalents (TE)/g among all of the foods, whereas lipophilic ORAC(FL) values (L-ORAC(FL)) ranged from 0.07 to 1611 micromol of TE/g. Generally, L-ORAC(FL) values were <10% of the H-ORAC(FL) values except for a very few samples. Total antioxidant capacity was calculated by combining L-ORAC(FL) and H-ORAC(FL). Differences of ORAC(FL) values in fruits and vegetables from different seasons and regions were relatively large for some foods but could not be analyzed in detail because of the sampling scheme. Two different processing methods, cooking and peeling, were used on selected foods to evaluate the impact of processing on ORAC(FL). The data demonstrated that processing can have significant effects on ORAC(FL). Considering all of the foods analyzed, the relationship between TP and H-ORAC(FL) showed a very weak correlation. Total hydrophilic and lipophilic antioxidant capacity intakes were calculated to be 5558 and 166 micromol of TE/day, respectively, on the basis of data from the USDA Continuing Survey of Food Intakes by Individuals (1994-1996).

N-terminal acylation of somatostatin analog with long chain fatty acids enhances its stability and anti-proliferative activity in human breast adenocarcinoma cells.

PubMed

Dasgupta, Piyali; Singh, Anu; Mukherjee, Rama

2002-01-01

The anti-proliferative activity of the somatostatin analog RC-160 is limited by its short serum half life. To circumvent this limitation, fatty acids of chain lengths ranging from 4 to 18 were individually conjugated to the N-terminal residue of RC-160. The lipophilized derivatives of RC-160 were synthesized, purified and characterized. The anti-proliferative activity of lipophilized-RC-160 on the human breast carcinoma cell line MCF-7, was evaluated in vitro. The long chain lipopeptides like pamitoyl-RC-160 exhibited significantly higher anti-proliferative activity on MCF-7 cells (p<0.001), relative to RC-160. The affinity of RC-160 towards somatostatin receptors remained unaltered by pamitoylation. However, the observed increase in bioactivity was manifested within an optimum range of chain length of the lipoppetide. Increasing the peptide hydrophobicity beyond this range reduced the bioactivity of lipophilized-RC-160. Accordingly, stearoyl-RC-160, manifested lower anti-neoplastic activity and receptor affinity relative to pamitoyl-RC-160 and RC-160 itself. The signaling pathways underlying the antineoplastic activity of these lipopeptides were found to be similar to RC-160. Pamitoyl-RC-160 displayed enhanced inhibition of protein tyrosine kinase activity and intracellular cAMP levels in MCF-7 cells, relative to butanoyl-RC-160 or RC-160 itself. Pamitoyl-RC-160 also displayed greater resistance towards trypsin and serum degradation than RC-160. Lipophilization of RC-160 with long chain fatty acids like pamitic acid improves its stability and anti-proliferative activity, thereby improving the scope of enhancing its therapeutic index. However, the optimization of peptide hydrophobicity seems to be a crucial factor governing the efficacy of bioactive lipopeptides.

Effect of lipophilicity on the bioavailability of drugs after percutaneous administration by dissolving microneedles.

PubMed

Ito, Yukako; Yoshimura, Masahiro; Tanaka, Tsutomu; Takada, Kanji

2012-03-01

To elucidate drug lipophilicity effects on the bioavailability (BA) of drugs from skin after administration by dissolving microneedles, nine compounds with different lipophilicity indexes (log p value) were formulated into two-layered dissolving microneedles and administered percutaneously to rat skin: desmopressin (DDAVP), sumatriptan (ST), fluorescein (FL), granisetron (GRN), pindolol (PDL), pravastatin (PRV), rhodamine 123 (Rho), rifampicin (RFP), and salmeterol (SLM). Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry and spectrofluorometry. In vivo dissolution and diffusion in both horizontal and vertical directions of FL and RH in the skin were studied using fluorescence microscopy. Respective BAs were 95.1 ± 7.9% (DDAVP), 84.2 ± 2.7% (ST), 82.3 ± 7.2% (FL), 82.7 ± 6.7% (GRN), 71.6 ± 3.8% (PDL), 63.6 ± 7.5% (PRV), 53.7 ± 8.3% (Rho), 46.2 ± 6.1% (RFP), and 38.4 ± 2.7% (SM). BA decreased as the lipophilicity index, log p value, of the drug increased from-1.95 to 1.73. The respective remaining percentages in skin tissue were 1.4 ± 0.7% (DDAVP), 0.9 ± 0.1% (ST), 1.0 ± 0.2% (FL), 3.4 ± 1.2% (GRN), 14.5 ± 3.7% (PDL), 23.4 ± 5.2% (PRV), 32.2 ± 6.0% (Rho), 40.7 ± 4.9% (RFP), and 40.6 ± 5.1% (SLM), dependent on log p. Fluorescence microscopy showed no FL or Rho in skin tissue within 4 and 24 h after administration, respectively. The BA of drugs delivered by dissolving microneedles depends on the drug solubility in the skin epidermis and dermis. Copyright © 2011 Wiley Periodicals, Inc.

Mechanism of transdermal permeation promotion of lipophilic drugs by ethosomes.

PubMed

Yang, Li; Wu, Lifang; Wu, Dongze; Shi, Deshun; Wang, Tai; Zhu, Xiaoliang

2017-01-01

Ethosomes can promote the penetration of lipophilic drugs into the skin, but the underlying mechanism is still unknown. The purpose of this study was to investigate the mechanism of transdermal permeation promotion of lipophilic drugs by ethosomes. The formulation of ethosomes was optimized using the Box-Behnken experimental design, in which Rhodamine B and 1-palmitoyl-2-{12-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl}- sn -glycero-3-phosphocholine were used to simulate a model lipophilic drug and act as a fluorescent tracer of ethosomal phospholipids, respectively. Liposomes with the same phospholipid concentration and a hydroethanolic solution with the same ethanol concentration were also prepared as controls. The percutaneous progression of the above fluorescent preparations was observed by confocal laser scanning microscopy, and the fluorescence intensity of the images was analyzed. The optimized ethosome formulation consisted of 2.45% yolk phospholipids, 30% ethanol, and 67.55% distilled water. The percutaneous permeation of Rhodamine B in the optimized ethosomes was superior to that in hydroethanolic solution ( P <0.05) and liposomes ( P <0.05). The ethosomes could penetrate the skin via the percutaneous pathway of the hair follicle and stratum corneum, while during the process of penetration, the vesicles were broken and the phospholipids were retained in the upper epidermis, with the test compounds penetrating gradually. The superior percutaneous penetration of ethosomes was linked to the synergistic effects of their ingredients. The percutaneous pathways of ethosomes included open hair follicles and stratum corneum pathways. In addition, the vesicles might break up during percutaneous penetration in the superficial layer of the skin, allowing the test compounds to keep permeating into the deeper layer alone, while the phospholipid was retained in the upper epidermis.

Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye.

PubMed

Loftsson, Thorsteinn; Stefánsson, Einar

2002-04-01

Cyclodextrins are cylindrical oligosaccharides with a lipophilic central cavity and hydrophilic outer surface. They can form water-soluble complexes with lipophilic drugs, which 'hide' in the cavity. Cyclodextrins can be used to form aqueous eye drop solutions with lipophilic drugs, such as steroids and some carbonic anhydrase inhibitors. The cyclodextrins increase the water solubility of the drug, enhance drug absorption into the eye, improve aqueous stability and reduce local irritation. Cyclodextrins are useful excipients in eye drop formulations of various drugs, including steroids of any kind, carbonic anhydrase inhibitors, pilocarpine, cyclosporins, etc. Their use in ophthalmology has already begun and is likely to expand the selection of drugs available as eye drops. In this paper we review the properties of cyclodextrins and their application in eye drop formulations, of which their use in the formulation of dexamethasone eye drops is an example. Cyclodextrins have been used to formulate eye drops containing corticosteroids, such as dexamethasone, with levels of concentration and ocular absorption which, according to human and animal studies, are many times those seen with presently available formulations. Cyclodextrin-based dexamethasone eye drops are well tolerated in the eye and seem to provide a higher degree of bioavailability and clinical efficiency than the steroid eye drop formulations presently available. Such formulations offer the possibility of once per day application of corticosteroid eye drops after eye surgery, and more intensive topical steroid treatment in severe inflammation. While cyclodextrins have been known for more than a century, their use in ophthalmology is just starting. Cyclodextrins are useful excipients in eye drop formulations for a variety of lipophilic drugs. They will facilitate eye drop formulations for drugs that otherwise might not be available for topical use, while improving absorption and stability and decreasing local irritation.

Lung Surfactant Microbubbles Increase Lipophilic Drug Payload for Ultrasound-Targeted Delivery

PubMed Central

Sirsi, Shashank R.; Fung, Chinpong; Garg, Sumit; Tianning, Mary Y.; Mountford, Paul A.; Borden, Mark A.

2013-01-01

The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta®, Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery. Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers. Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy. The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C. Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities. At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release. To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber. Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles. Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload. PMID:23781287

Lung surfactant microbubbles increase lipophilic drug payload for ultrasound-targeted delivery.

PubMed

Sirsi, Shashank R; Fung, Chinpong; Garg, Sumit; Tianning, Mary Y; Mountford, Paul A; Borden, Mark A

2013-01-01

The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta(®), Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery. Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers. Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy. The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C. Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities. At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release. To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber. Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles. Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload.

Lipophilicity, antifungal and antioxidant properties of persilben.

PubMed

Smolarz, Helena D; Kosikowska, Urszula; Baraniak, Barbara; Malm, Anna; Persona, Andrzej

2005-01-01

The lipophilicity of persilben, an important parameter influencing the penetration of the compound through biological membranes, was determined experimentally by dynamic method and was theoretically calculated according to the fragmentation methods introduced by Crippen, Broto and Viswanadhan. The higher value of partition coefficient (log P = 3.89) obtained for persilben than that for resveratrol points to potentially higher ease of penetration of persilben into cells of living organism. Antimicrobial and antioxidant activities of persilben were tested. The obtained data suggest that this compound possesses some antioxidant activity. Persilben appears to have also some inhibitory effect against some species of dermatophytes from Tnichophyton genus but only at high concentrations.

The connection Between Plasma Protein Binding and Acute Toxicity as Determined by the LD50 Value.

PubMed

Svennebring, Andreas

2016-02-01

Preclinical Research A dataset of three drug classes (acids, bases, and neutrals) with LD50 values in mice was analysed to investigate a possible connection between high plasma protein binding and acute toxicity. Initially, it was found that high plasma protein binding was associated with toxicity for acids and neutrals, but after compensating for differences in lipophilicity, plasma protein binding was found not to be associated with toxicity. The therapeutic index established by the quotient between mouse LD50 and the defined daily dose was unaffected by both lipophilicity and plasma protein binding. © 2015 Wiley Periodicals, Inc.

Diffusion and imaging properties of three new lipophilic tracers, NeuroVue ™ Maroon, NeuroVue ™ Red and NeuroVue ™ Green and their use for double and triple labeling of neuronal profile.

PubMed Central

Fritzsch, B.; Muirhead, K.A.; Feng, Feng; D.Gray, B.; Ohlsson-Wilhelm, B. M.

2006-01-01

We describe here diffusion and imaging properties of three new lipophilic tracers, NeuroVue ™ Maroon (near infrared), NeuroVue ™ Red and NeuroVue ™ Green. Using pair wise comparisons between the new dyes and existing dyes (DiI, DiA, DiD, DiO, PKH2, PKH26) applied to the left and the right side of fixed spinal cord preparations, we show that NeuroVue Maroon (excitation max 647 nm) surpasses all other dyes in this study in signal to noise ratio. We also present data showing the utility of these new dyes for both double labeling and triple labeling in combination with each other or existing lipophilic tracers. Using mice bearing the PLP-eGFP transgene, we demonstrate that either NeuroVue Maroon or NeuroVue Red can readily be combined with eGFP labeling. Double labeling experiments using NeuroVue Red and eGFP allowed us to demonstrate that every fiber in the neonatal ear is surrounded by developing Schwann cells. PMID:16023922

Experimental validation of a model for diffusion-controlled absorption of organic compounds in the trachea

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerde, P.; Muggenburg, B.A.; Thornton-Manning, J.R.

1995-12-01

Most chemically induced lung cancer originates in the epithelial cells in the airways. Common conceptions are that chemicals deposited on the airway surface are rapidly absorbed through mucous membranes, limited primarily by the rate of blood perfusion in the mucosa. It is also commonly thought that for chemicals to induce toxicity at the site of entry, they must be either rapidly reactive, readily metabolizable, or especially toxic to the tissues at the site of entry. For highly lipophilic toxicants, there is a third option. Our mathematical model predicts that as lipophilicity increases, chemicals partition more readily into the cellular lipidmore » membranes and diffuse more slowly through the tissues. Therefore, absorption of very lipophilic compounds will be almost entirely limited by the rate of diffusion through the epithelium rather than by perfusion of the capillary bed in the subepithelium. We have reported on a preliminary model for absorption through mucous membranes of any substance with a lipid/aqueous partition coefficient larger than one. The purpose of this work was to experimentally validate the model in Beagle dogs. This validated model on toxicant absorption in the airway mucosa will improve risk assessment of inhaled« less

Measurement of diffusion coefficients of parabens and steroids in water and 1-octanol.

PubMed

Seki, Toshinobu; Mochida, Junko; Okamoto, Maiko; Hosoya, Osamu; Juni, Kazuhiko; Morimoto, Kazuhiro

2003-06-01

Diffusion coefficients (D) of parabens and steroids in water and 1-octanol were determined by using the chromatographic broadening method at 37 degrees C, and the relationships between the D values and the physicochemical properties of the drugs were discussed. The D values in 1-octanol were lower than those in water because of the higher viscosity of 1-octanol. The D values depend on not only the molecular weight (MW), but also the lipophilicity of the drugs in water and on the ability for hydrogen-bonding in 1-octanol. When the lipophilic index (LI), calculated from the retention time using in a reverse-phase column, was used as a parameter of drug lipophilicity, the following equation was obtained for D in water (D(w)); log D(w)=-0.215.log MW-0.077.log LI-4.367. When the hydrogen bond index (HI), the logarithm of the ratio of the partition coefficient of the drugs in 1-octanol and cyclohexane, was used as an index of hydrogen-bonding, the following equation was obtained for D in 1-octanol (D(o)); log D(o)=-0.690.log MW-0.074.log HI-4.085.

Evaluation of Organogel Nanoparticles as Drug Delivery System for Lipophilic Compounds.

PubMed

Martin, Baptiste; Brouillet, Fabien; Franceschi, Sophie; Perez, Emile

2017-05-01

The purpose of the study was to evaluate organogel nanoparticles as a drug delivery system by investigating their stability, according to the formulation strategy, and their release profile. The gelled nanoparticles were prepared by hot emulsification (above the gelation temperature) of an organogel in water, and cooling at room temperature. In the first step, we used DLS and DSC to select the most suitable formulations by optimizing the proportion of ingredients (HSA, PVA, castor oil) to obtain particles of the smallest size and greatest stability. Then, two lipophilic drug models, indomethacin and ketoconazole were entrapped in the nanoparticles made of castor oil gelled by 12-hydroxystearic acid. Thermal studies (DSC) confirmed that there was no significant alteration of gelling due to the entrapped drugs, even at 3% w/w. Very stable dispersions were obtained (>3 months), with gelled oil nanoparticles presenting a mean diameter between 250 and 300 nm. High encapsulation efficiency (>98%) was measured for indomethacin and ketoconazole. The release profile determined by in vitro dialysis showed an immediate release of the drug from the organogel nanoparticles, due to rapid diffusion. The study demonstrates the interest of these gelled oil nanoparticles for the encapsulation and the delivery of lipophilic active compounds.

Double Transfer Voltammetry in Two-Polarizable Interface Systems: Effects of the Lipophilicity and Charge of the Target and Compensating Ions.

PubMed

Molina, Ángela; Laborda, Eduardo; Olmos, José Manuel; Millán-Barrios, Enrique

2018-03-06

Analytical expressions are obtained for the study of the net current and individual fluxes across macro- and micro-liquid/liquid interfaces in series as those found in ion sensing with solvent polymeric membranes and in ion-transfer batteries. The mathematical solutions deduced are applicable to any voltammetric technique, independently of the lipophilicity and charge number of the target and compensating ions. When supporting electrolytes of semihydrophilic ions are employed, the so-called double transfer voltammograms have a tendency to merge into a single signal, which complicates notably the modeling and analysis of the electrochemical response. The present theoretical results point out that the appearance of one or two voltammetric waves is highly dependent on the size of the interfaces and on the viscosity of the organic solution. Hence, the two latter can be adjusted experimentally in order to "split" the voltammograms and extract information about the ions involved. This has been illustrated in this work with the experimental study in water | 1,2-dichloroethane | water cells of the transfer of the monovalent tetraethylammonium cation compensated by anions of different lipophilicity, and also of the divalent hexachloroplatinate anion.

[Testing the pharmacological activity of some synthetic cannabinoids in mice (author's transl)].

PubMed

Ganz, A J; Waser, P G

1980-01-01

A series of synthetic cannabinoids were tested in mice for analgesic, anticonvulsant, sedative and reserpine antagonistic properties as well as for influence on body temperature and on motor coordination and compared with the natural delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC) and cannabidiol (CBD). All cannabinoids were injected s.c. or i.p. in mice as solutions in olive oil. The synthetic cannabinoids, with the exception of the lipophilic ones, were less active than the natural delta 9-THC. 1',1'-dimethyl-delta 8-tetrahydrocannabinol (DM-delta 8-THC) has an analgesic ED 50 of 16 mg/kg s.c. (writhing test) and is three times more active than delta 9-THC, but also eight times less active than morphine. The lipophilic derivatives of delta 8-THC prolonged pentobarbitone narcosis and diminished locomotor activity in mice. Anticonvulsant activities could never be detected; all cannabinoids slightly diminished body temperature and antagonized weakly the hypothermia induced by reserpine. The trained capacity of remaining on the rotating rod was severely shortened for a long time after application of all cannabinoids but mainly by the lipophilic ones. The influence of derivation on the activity of delta 9-THC is discussed.

Multi-parameter optimization of aza-follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 2: Impact of lipophilicity on promiscuity and in vivo toxicity.

PubMed

Beaulieu, Pierre L; Bolger, Gordon; Deon, Dan; Duplessis, Martin; Fazal, Gulrez; Gagnon, Alexandre; Garneau, Michel; LaPlante, Steven; Stammers, Timothy; Kukolj, George; Duan, Jianmin

2015-03-01

We describe our efforts to identify analogs of thumb pocket 1 HCV NS5B inhibitor 1 (aza-analog of BI 207524) with improved plasma to liver partitioning and a predicted human half-life consistent with achieving a strong antiviral effect at a reasonable dose in HCV-infected patients. Compounds 3 and 7 were identified that met these criteria but exhibited off-target promiscuity in an in vitro pharmacology screen and in vivo toxicity in rats. High lipophilicity in this class was found to correlate with increased probability for promiscuous behavior and toxicity. The synthesis of an 8×11 matrix of analogs allowed the identification of C3, an inhibitor that displayed comparable potency to 1, improved partitioning to the liver and reduced lipophilicity. Although C3 displayed reduced propensity for in vitro off-target inhibition and the toxicity profile in rats was improved, the predicted human half-life of this compound was short, resulting in unacceptable dosing requirements to maintain a strong antiviral effect in patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Inhibition of human dendritic cell activation by hydroethanolic but not lipophilic extracts of turmeric (Curcuma longa).

PubMed

Krasovsky, Joseph; Chang, David H; Deng, Gary; Yeung, Simon; Lee, Mavis; Leung, Ping Chung; Cunningham-Rundles, Susanna; Cassileth, Barrie; Dhodapkar, Madhav V

2009-03-01

Turmeric has been extensively utilized in Indian and Chinese medicine for its immune-modulatory properties. Dendritic cells (DCs) are antigen-presenting cells specialized to initiate and regulate immunity. The ability of DCs to initiate immunity is linked to their activation status. The effects of turmeric on human DCs have not been studied. Here we show that hydroethanolic (HEE) but not lipophilic "supercritical" extraction (SCE) of turmeric inhibits the activation of human DCs in response to inflammatory cytokines. Treatment of DCs with HEE also inhibits the ability of DCs to stimulate the mixed lymphocyte reaction (MLR). Importantly, the lipophilic fraction does not synergize with the hydroethanolic fraction for the ability of inhibiting DC maturation. Rather, culturing of DCs with the combination of HEE and SCE leads to partial abrogation of the effects of HEE on the MLR initiated by DCs. These data provide a mechanism for the anti-inflammatory properties of turmeric. However, they suggest that these extracts are not synergistic and may contain components with mutually antagonistic effects on human DCs. Harnessing the immune effects of turmeric may benefit from specifically targeting the active fractions.

Inhibition of Human Dendritic Cell Activation by Hydroethanolic But Not Lipophilic Extracts of Turmeric (Curcuma longa)

PubMed Central

Krasovsky, Joseph; Chang, David H.; Deng, Gary; Yeung, Simon; Lee, Mavis; Leung, Ping Chung; Cunningham-Rundles, Susanna; Cassileth, Barrie; Dhodapkar, Madhav V.

2015-01-01

Turmeric has been extensively utilized in Indian and Chinese medicine for its immune-modulatory properties. Dendritic cells (DCs) are antigen-presenting cells specialized to initiate and regulate immunity. The ability of DCs to initiate immunity is linked to their activation status. The effects of turmeric on human DCs have not been studied. Here we show that hydroethanolic (HEE) but not lipophilic “supercritical” extraction (SCE) of turmeric inhibits the activation of human DCs in response to inflammatory cytokines. Treatment of DCs with HEE also inhibits the ability of DCs to stimulate the mixed lymphocyte reaction (MLR). Importantly, the lipophilic fraction does not synergize with the hydroethanolic fraction for the ability of inhibiting DC maturation. Rather, culturing of DCs with the combination of HEE and SCE leads to partial abrogation of the effects of HEE on the MLR initiated by DCs. These data provide a mechanism for the anti-inflammatory properties of turmeric. However, they suggest that these extracts are not synergistic and may contain components with mutually antagonistic effects on human DCs. Harnessing the immune effects of turmeric may benefit from specifically targeting the active fractions. PMID:19034830

Fast log P determination by ultra-high-pressure liquid chromatography coupled with UV and mass spectrometry detections.

PubMed

Henchoz, Yveline; Guillarme, Davy; Martel, Sophie; Rudaz, Serge; Veuthey, Jean-Luc; Carrupt, Pierre-Alain

2009-08-01

Ultra-high-pressure liquid chromatography (UHPLC) systems able to work with columns packed with sub-2 microm particles offer very fast methods to determine the lipophilicity of new chemical entities. The careful development of the most suitable experimental conditions presented here will help medicinal chemists for high-throughput screening (HTS) log P(oct) measurements. The approach was optimized using a well-balanced set of 38 model compounds and a series of 28 basic compounds such as beta-blockers, local anesthetics, piperazines, clonidine, and derivatives. Different organic modifiers and hybrid stationary phases packed with 1.7-microm particles were evaluated in isocratic as well as gradient modes, and the advantages and limitations of tested conditions pointed out. The UHPLC approach offered a significant enhancement over the classical HPLC methods, by a factor 50 in the lipophilicity determination throughput. The hyphenation of UHPLC with MS detection allowed a further increase in the throughput. Data and results reported herein prove that the UHPLC-MS method can represent a progress in the HTS-measurement of lipophilicity due to its speed (at least a factor of 500 with respect to HPLC approaches) and to an extended field of application.

The Brown Alga Stypopodium zonale (Dictyotaceae): A Potential Source of Anti-Leishmania Drugs

PubMed Central

Soares, Deivid Costa; Szlachta, Marcella Macedo; Teixeira, Valéria Laneuville; Soares, Angelica Ribeiro; Saraiva, Elvira Maria

2016-01-01

This study evaluated the anti-Leishmania amazonensis activity of a lipophilic extract from the brown alga Stypopodium zonale and atomaric acid, its major compound. Our initial results revealed high inhibitory activity for intracellular amastigotes in a dose-dependent manner and an IC50 of 0.27 μg/mL. Due to its high anti-Leishmania activity and low toxicity toward host cells, we fractionated the lipophilic extract. A major meroditerpene in this extract, atomaric acid, and its methyl ester derivative, which was obtained by a methylation procedure, were identified by nuclear magnetic resonance (NMR) spectroscopy. Both compounds inhibited intracellular amastigotes, with IC50 values of 20.2 μM (9 μg/mL) and 22.9 μM (10 μg/mL), and selectivity indexes of 8.4 μM and 11.5 μM. The leishmanicidal activity of both meroditerpenes was independent of nitric oxide (NO) production, but the generation of reactive oxygen species (ROS) may be at least partially responsible for the amastigote killing. Our results suggest that the lipophilic extract of S. zonale may represent an important source of compounds for the development of anti-Leishmania drugs. PMID:27618071

Analysis of Physicochemical Properties for Drugs of Natural Origin.

PubMed

Camp, David; Garavelas, Agatha; Campitelli, Marc

2015-06-26

The impact of time, therapy area, and route of administration on 13 physicochemical properties calculated for 664 drugs developed from a natural prototype was investigated. The mean values for the majority of properties sampled over five periods from pre-1900 to 2013 were found to change in a statistically significant manner. In contrast, lipophilicity and aromatic ring count remained relatively constant, suggesting that these parameters are the most important for successful prosecution of a natural product drug discovery program if the route of administration is not focused exclusively on oral availability. An examination by therapy area revealed that anti-infective agents had the most differences in physicochemical property profiles compared with other areas, particularly with respect to lipophilicity. However, when this group was removed, the variation between the mean values for lipophilicity and aromatic ring count across the remaining therapy areas was again found not to change in a meaningful manner, further highlighting the importance of these two parameters. The vast majority of drugs with a natural progenitor were formulated for either oral and/or injectable administration. Injectables were, on average, larger and more polar than drugs developed for oral, topical, and inhalation routes.

Lipophilization of somatostatin analog RC-160 with long chain fatty acid improves its anti-proliferative activity on human oral carcinoma cells in vitro.

PubMed

Dasgupta, P; Singh, A T; Mukherjee, R

2000-03-01

Oral cancer which comprises about 40% of total cancers in India, has one of the lowest relative survival rates of all cancers. Epidermal growth factor (EGF) has been known to play a role in the proliferation/malignant transformation of oral neoplasms. Since, the somatostatin analog RC-160 is reported to be a potent inhibitor of EGF stimulated cell proliferation, its anti-proliferative activity in the human oral carcinoma cell line KB was investigated, in this study. RC-160 was found to potently inhibit EGF-induced proliferation in KB cells in vitro, suggesting a therapeutic potential of the same in oral carcinoma. However, the therapeutic potential of RC-160 is limited by its short serum half life. To overcome this limitation, fatty acids namely butanoic acid and myristic acid individually were coupled to RC-160. The lipophilized derivatives of RC-160 were synthesized, purified and characterized. The anti-proliferative activity of lipophilized derivatives of RC-160 on KB cells was evaluated in vitro. Myristoyl-RC-160 (0.75 nM) inhibited the growth of KB cells at a 10-fold lower concentration relative to RC-160 (8.8 nM) and at a 100-fold lower concentration relative to butanoyl-RC-160 (0.83 microM) (p<0.001). The affinity of RC-160 towards somatostatin receptors remains unaltered by lipophilization. The signaling pathways underlying the antineoplastic activity of these lipopeptides are similar to RC-160, and do not involve the stimulation of a protein tyrosine phosphatase or a serine threonine phosphatase 1A and 2A. The anti-proliferative activity of the lipopeptides was found to be mediated by somatostatin receptors and correlates with the inhibition of protein tyrosine kinase activity and decrease in intracellular cAMP levels. Myristoyl-RC-160 displayed significantly greater resistance towards trypsin and serum degradation than RC-160 (p<0.01). These findings demonstrate that RC-160 can inhibit the growth of oral cancer cells in vitro. Lipophilization of RC-160 with long chain fatty acids like myristic acid improves its stability and anti-proliferative activity, in human oral carcinoma cells in vitro, thereby enhancing the scope of improving its therapeutic index.

A Fiber Optic Ammonia Sensor Using a Universal pH Indicator

PubMed Central

Rodríguez, Adolfo J.; Zamarreño, Carlos R.; Matías, Ignacio R.; Arregui, Francisco. J.; Domínguez Cruz, Rene F.; May-Arrioja, Daniel. A.

2014-01-01

A universal pH indicator is used to fabricate a fiber optic ammonia sensor. The advantage of this pH indicator is that it exhibits sensitivity to ammonia over a broad wavelength range. This provides a differential response, with a valley around 500 nm and a peak around 650 nm, which allows us to perform ratiometric measurements. The ratiometric measurements provide not only an enhanced signal, but can also eliminate any external disturbance due to humidity or temperature fluctuations. In addition, the indicator is embedded in a hydrophobic and gas permeable polyurethane film named Tecoflex®. The film provides additional advantages to the sensor, such as operation in dry environments, efficient transport of the element to be measured to the sensitive area of the sensor, and prevent leakage or detachment of the indicator. The combination of the universal pH indicator and Tecoflex® film provides a reliable and robust fiber optic ammonia sensor. PMID:24583969

TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors

PubMed Central

Sethuraman, Vijay A; Bae, You Han

2007-01-01

A novel drug targeting system for acidic solid tumors has been developed based on ultra pH sensitive polymer and cell penetrating TAT. The delivery system consisted of two components: 1) A polymeric micelle that has a hydrophobic core made of Poly(L-lactic acid) (PLLA) and a hydrophilic shell consisting of Polyethylene Glycol (PEG) conjugated to TAT (TATmicelle), 2) An ultra pH sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and PEG (PSD-b-PEG). The anionic PSD is complexed with cationic TAT of the micelles to achieve the final carrier, which could systemically shield the micelles and expose them at slightly acidic tumor pH. TATmicelles had particle sizes between 20 to 45 nm and their critical micelle concentrations were 3.5 mg/L to 5.5 mg/L. The TATmicelles, upon mixing with pH sensitive PSD-b-PEG, showed slight increase in particle size between pH 8.0 and 6.8 (60–90 nm), indicating complexation. As the pH was decreased (pH 6.6 to 6.0) two populations were observed, one that of normal TAT micelles (45 nm) and the other of aggregated hydrophobic PSD-b-PEG. Zeta potential measurements showed similar trend substantiating the shielding/deshielding process. Flowcytometry and confocal microscopy showed significantly higher uptake of TAT micelles at pH 6.6 compared to pH 7.4 indicating shielding at normal pH and deshielding at tumor pH. The flowcytometry indicated that the TAT not only translocates into the cells but is also seen on the surface of the nucleus. These results strongly indicate that the above drug loaded micelles would be able to target any hydrophobic drug near the nucleus. PMID:17239466

Edwardsiella ictaluri Encodes an Acid-Activated Urease That Is Required for Intracellular Replication in Channel Catfish (Ictalurus punctatus) Macrophages▿

PubMed Central

Booth, Natha J.; Beekman, Judith B.; Thune, Ronald L.

2009-01-01

Genomic analysis indicated that Edwardsiella ictaluri encodes a putative urease pathogenicity island containing the products of nine open reading frames, including urea and ammonium transporters. In vitro studies with wild-type E. ictaluri and a ureG::kan urease mutant strain indicated that E. ictaluri is significantly tolerant of acid conditions (pH 3.0) but that urease activity is not required for acid tolerance. Growth studies demonstrated that E. ictaluri is unable to grow at pH 5 in the absence of urea but is able to elevate the environmental pH from pH 5 to pH 7 and grow when exogenous urea is available. Substantial production of ammonia was observed for wild-type E. ictaluri in vitro in the presence of urea at low pH, and optimal activity occurred at pH 2 to 3. No ammonia production was detected for the urease mutant. Proteomic analysis with two-dimensional gel electrophoresis indicated that urease proteins are expressed at both pH 5 and pH 7, although urease activity is detectable only at pH 5. Urease was not required for initial invasion of catfish but was required for subsequent proliferation and virulence. Urease was not required for initial uptake or survival in head kidney-derived macrophages but was required for intracellular replication. Intracellular replication of wild-type E. ictaluri was significantly enhanced when urea was present, indicating that urease plays an important role in intracellular survival and replication, possibly through neutralization of the acidic environment of the phagosome. PMID:19749068

Direct fluorination of phenolsulfonphthalein: a method for synthesis of positron-emitting indicators for in vivo pH measurement

PubMed Central

Kachur, Alexander V.; Popov, Anatoliy V.; Karp, Joel S.; Delikatny, E. James

2014-01-01

We report a reaction of direct electrophilic fluorination of phenolsulfonphthalein at mild conditions. This reaction affords the synthesis of novel positron-emitting 18F-labeled pH indicators. These compounds are useful for non-invasive in vivo pH measurement in biological objects. PMID:22790882